Antithrombotic aromatic ethers

ABSTRACT

This application relates to a compound of formula I (or a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa and/or thrombin, as well as a process for its preparation and intermediates therefor.

This application claims the benefit of U.S. Provisional Application No.60/507,439, filed Sep. 30, 2003, which is incorporated by referenceherein in its entirety.

This invention relates to antithrombotic aromatic ethers whichdemonstrate activity as inhibitors of thrombin and/or factor Xa and,accordingly, which are useful antithrombotics in mammals. In particularit relates to antithrombotic aromatic ethers having high anticoagulantactivity, good oral exposure and antithrombotic activity. Thus, thisinvention relates to new antithrombotic aromatic ethers which areinhibitors of thrombin and/or factor Xa, pharmaceutical compositionscontaining the antithrombotic aromatic ethers as active ingredients, andthe use of the antithrombotic aromatic ethers as anticoagulants forprophylaxis and treatment of thromboembolic disorders such as venousthrombosis, pulmonary embolism, arterial thrombosis, in particularmyocardial ischemia, myocardial infarction and cerebral thrombosis,general hypercoagulable states and local hypercoagulable states, such asfollowing angioplasty and coronary bypass operations, and generalizedtissue injury as it relates to the inflammatory process. In addition,the antithrombotic aromatic ethers are useful as anticoagulants in invitro applications.

The process of blood coagulation, thrombosis, is triggered by a complexproteolytic cascade leading to the formation of thrombin. Thrombinproteolytically removes activation peptides from the Aa-chains and theBP-chains of fibrinogen, which is soluble in blood plasma, initiatinginsoluble fibrin formation. The formation of thrombin from prothrombinis catalyzed by factor Xa.

Anticoagulation currently is achieved by the administration of heparinsand coumarins. Parenteral pharmacological control of coagulation andthrombosis is based on inhibition of thrombin through the use ofheparins. Heparins act indirectly on thrombin by accelerating theinhibitory effect of endogenous antithrombin III (the main physiologicalinhibitor of thrombin). Because antithrombin III levels vary in plasmaand because clot-bound thrombin seems resistant to this indirectmechanism, heparins can be an ineffective treatment. Because coagulationassays are believed to be associated with efficacy and with safety,heparin levels must be monitored with coagulation assays (particularlythe activated partial thromboplastin time (APTT) assay). Coumarinsimpede the generation of thrombin by blocking the posttranslationalgamma-carboxylation in the synthesis of prothrombin and other proteinsof this type. Because of their mechanism of action, the effect ofcoumarins can only develop slowly, 6-24 hours after administration.Further, they are not selective anticoagulants. Coumarins also requiremonitoring with coagulation assays (particularly the prothrombin time(PT) assay).

Recently, interest has grown in small synthetic molecules whichdemonstrate potent direct inhibition of thrombin and factor Xa. See, forexample, B. Y. Zhu and R. M. Scarborough, Annual Reports in MedicinalChemistry, (2000), 35, 83-102, Factor Xa Inhibitors: Recent Advances inAnticoagulant Agents.

Although the heparins and coumarins are effective anticoagulants, therestill exists a need for anticoagulants which act selectively on factorXa and/or thrombin, and which, independent of antithrombin III, exertinhibitory action shortly after administration, preferably by an oralroute, and do not interfere with lysis of blood clots, as required tomaintain hemostasis.

The present invention is directed to the discovery that theantithrombotic aromatic ethers of the present invention, as definedbelow, are potent inhibitors of thrombin and/or factor Xa which may havehigh bioavailability following oral administration.

According to the invention there is provided a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein:

A³, A⁴, A⁵ and A⁶, together with the two carbons to which they areattached, complete a substituted heteroaromatic ring in which

one of A³, A⁴, A⁵ and A⁶ is N, and each of the others is CR³, CR⁴, CR⁵or CR⁶, respectively; wherein

each of R³, R⁴, R⁵ and R⁶ is hydrogen; or one or more of R³, R⁴, R⁵ andR⁶ is methyl each of the others is hydrogen; or one of R³, R⁴, R⁵ and R⁶attached to a carbon which is not bonded to an N-atom is chloro and eachof the others are hydrogen; or

two adjacent residues of A³, A⁴, A⁵ and A⁶ together form S, and each ofthe others is CH;

L is carbonyl or methylene;

R is 2-pyridinyl (which may bear a methyl, cyano, carbamoyl,hydroxymethyl, formyl, vinyl, amino, hydroxy, methoxy, difluoromethoxy,methylthio, fluoro or chloro substituent at the 5-position), or R is3-pyridinyl (which may bear a methyl, fluoro or chloro substituent atthe 6-position), or R is 2-thiazolyl (which may bear a methylsubstituent at the 4-position or a bromo substituent at the 5-position),or R is phenyl (which may bear one, two or three substituents at the 3-,4- or 5-position(s) independently selected from fluoro, chloro, bromo,cyano, carbamoyl, methyl, methoxy, difluoromethoxy, hydroxymethyl,formyl, vinyl, amino, hydroxy and 3,4-methylenedioxy; and in additionthe phenyl may bear a 2-chloro or 2-fluoro substituent), or R is6-indolyl (which may bear a chloro or methyl substituent at the3-position);

R¹ is —(CH₂)_(i)-Q-(CH₂)_(j)—NR^(a)R^(b) in which

a) Q is a single bond; the sum of i and j is 2 or 3; and each of R^(a)and R^(b) is hydrogen, or each of R^(a) and R^(b) is independently(1-3C) normal alkyl, or R^(a) is hydrogen and R^(b) is (1-3C)alkyl orformyl, or NR^(a)R^(b) is 1-pyrrolidinyl or 4-morpholinyl;

b) Q is —CH(CH₃)—, —C(CH₃)₂— or —CH(OH)—; each of i and j is 1; and eachof R^(a) and R^(b) is hydrogen, or each of R^(a) and R^(b) isindependently (1-3C) normal alkyl, or R^(a) is hydrogen and R^(b) is(1-3C)alkyl or formyl, or —NR^(a)R^(b) is 1-pyrrolidinyl or4-morpholinyl;

c) Q is cyclohexane-1,4-diyl; each of i and j is 0; R^(a) is hydrogen;and R^(b) is hydrogen or methyl;

d) Q is —CHR^(c)—; i is 0; j is 1; R^(a) is hydrogen or methyl; andR^(b) and R^(c) together are —(CH₂)_(k)— wherein k is 2 or 3;

e) Q is —CHR^(c)—; i is 1; j is 1; R^(a) is hydrogen or methyl; andR^(b) and R^(c) together are —(CH₂)_(k)— wherein k is 1, 2 or 3; or

f) Q is —CHR^(c)—; i is 0 or 1; j is 2; R^(a) is hydrogen or methyl; andR^(b) and R^(c) together are —(CH₂)_(k)— wherein k is 2; and

R² is fluoro, chloro, (1-4C)alkyl, —NR^(d)R^(e), —OR^(f), acetyl,—CONR^(g)R^(h) or NHCOR^(i) in which each of R^(d) and R^(e) isindependently hydrogen or (1-3C)alkyl; or —NR^(d)R^(e) is1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl,hexahydro-1,4-diazepin-1-yl or 4-morpholinyl (in which the 1-piperazinylor hexahydro-1,4-diazepin-1-yl may bear a 4-methyl substituent and the1-piperidinyl may bear one or two 4-methyl substituents); R^(f) is(1-3C)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or 2-methoxyethyl; eachof R^(g) and R^(h) is hydrogen, or R^(g) is hydrogen and R^(h) is(1-6C)alkyl or (3-6C)cycloalkyl, or each of R^(g) and R^(h) isindependently (1-3C)alkyl, or —NR^(g)R^(h) is 1-pyrrolidinyl,1-piperidinyl, 1-piperazinyl or 4-morpholinyl (in which the1-piperazinyl may bear a 4-methyl substituent and the 1-piperidinyl maybear one or two 4-methyl substituents); and R^(i) is hydrogen,(1-6C)alkyl or (3-6C)cycloalkyl.

As used herein, the expression a compound of formula I or the expressiona compound of the invention includes the compound and any conventionalprodrug thereof, as well as a pharmaceutically acceptable salt of saidcompound or prodrug.

In this specification, the following definitions are used, unlessotherwise described: Halo is fluoro, chloro, bromo or iodo. Alkyl,alkoxy, etc. denote both straight and branched groups; but reference toan individual radical such as “propyl” embraces only the straight chain(“normal”) radical, a branched chain isomer such as “isopropyl” beingspecifically denoted.

Particular values for the groups and ranges defined herein include thefollowing: (1-3C) normal alkyl is methyl, ethyl or propyl; (1-3C)alkylis methyl, ethyl, propyl, or isopropyl; (1-4C)alkyl is methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; (1-6C)alkylis methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyltert-butyl; pentyl, 3-methylbutyl, 1-ethylpropyl, hexyl, 4-methylpentylor 2-ethylbutyl; and (3-6C)cycloalkyl is cyclohexyl, cyclobutyl,cyclopentyl or cyclohexyl.

It will be appreciated that certain compounds of formula I (or salts orprodrugs, etc.) may, exist in, and be isolated in, isomeric forms,including tautomeric forms, cis- or trans-isomers, as well as opticallyactive, racemic, or diastereomeric forms. It is to be understood thatthe present invention encompasses a compound of formula I in any of thetautomeric forms or as an a mixture thereof; or as a mixture ofdiastereomers, as well as in the form of an individual diastereomer, andthat the present invention encompasses a compound of formula I as amixture of enantiomers, as well as in the form of an individualenantiomer, any of which mixtures or form possesses inhibitoryproperties against thrombin and/or factor Xa, it being well known in theart how to prepare or isolate particular forms and how to determineinhibitory properties against thrombin and/or factor xa by standardtests including those described below.

In addition, a compound of formula I (or salt or prodrug, etc.) mayexhibit polymorphism or may form a solvate with water or an organicsolvent. The present invention also encompasses any such polymorphicform, any solvate or any mixture thereof.

A prodrug of a compound of formula I may be one formed in a conventionalmanner with a functional group of the compound, such as with an amino,hydroxy or carboxy group.

One particular compound of formula I is one wherein

R is 2-pyridinyl, which bears a methyl, fluoro or chloro substituent atthe 5-position; or R is 2-thiazolyl, which may bear a methyl substituentat the 4-position or a bromo substituent at the 5-position, or R isphenyl, which may bear a fluoro, chloro or methoxy substituent at the4-position; or R is 6-indolyl;

R¹ is 2-aminoethyl, 2-(dimethylamino)ethyl, 2-(formylamino) ethyl,3-aminopropyl, 3-(formylamino)propyl, 3-(1-pyrrolidinyl)propyl,3-(4-morpholinyl)propyl, 3-amino-2-methylpropyl,3-amino-2,2-dimethylpropyl, 3-amino-2-hydroxypropyl,cis-4-aminocyclohexyl, cis-4-(methylamino)-cyclohexyl, 3-pyrrolidinyl,3-piperidinyl, 3-azetidinyl-methyl, 3-pyrrolidinylmethyl,3-piperidinylmethyl, 4-piperidinyl, 4-piperidinylmethyl or1-methyl-piperidin-4-yl; and

R² is fluoro, isopropyl, tert-butyl, dimethylamino, 1-pyrrolidinyl,1-piperidinyl, 1-piperazinyl, hexahydro-1,4-diazepin-1-yl,4-morpholinyl, methoxy, ethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy,2-methoxyethoxy or acetyl.

A more particular compound, or salt thereof, as described above is onewherein

R is 5-chloropyridin-2-yl, 2-thiazolyl, 4-methylthiazol-2-yl,5-bromothiazol-2-yl or 4-chlorophenyl;

R¹ is 2-aminoethyl, 2-(formylamino)ethyl, 3-amino-propyl,3-(formylamino)propyl, 3-amino-2,2-dimethylpropyl,cis-4-aminocyclohexyl, 3-piperidinylmethyl or 4-piperidinyl; and

R² is fluoro, isopropyl, tert-butyl, dimethylamino, 1-pyrrolidinyl,4-morpholinyl, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethoxy oracetyl.

A preferred compound, or salt thereof, as described above is one whereinfor R, R¹ and R²:

R is 5-chloropyridin-2-yl;

R¹ is 3-amino-2,2-dimethylpropyl, cis-4-amino-cyclohexyl, or4-piperidinyl; and

R² is 1-pyrrolidinyl, 4-morpholinyl, 2-fluoroethoxy or 2-methoxyethoxy.

One compound according to the above definitions is a pyridine in wherein

one of A³, A⁴, A⁵ and A⁶ is N, and each of the others is CR³, CR⁴, CR⁵or CR⁶, respectively; in which

each of R³, R⁴ and R⁶ is hydrogen and R⁵ is hydrogen or methyl, and,more particularly, wherein each of R³, R⁴, R⁵ and R⁶ is hydrogen.

One pyridine according to the above definitions is one wherein A³ is N.

Another pyridine according to the above definitions is one wherein A⁴ isN.

A further pyridine according to the above definitions is one wherein A⁵is N.

Another pyridine according to the above definitions is one wherein A⁶ isN.

Another particular compound or salt according to the above definitionsis one wherein A³, A⁴, A⁵ and A⁶, together with the two carbons to whichthey are attached, complete a substituted thiophene ring in which

(a) A³ and A⁶ are each CH; or

(b) A³ and A⁴ are each CH.

A particular compound or salt according to the above definitions is onewherein L is carbonyl.

Another particular compound or salt according to the above definitionsis one wherein L is methylene.

A specific compound, or pharmaceutically acceptable salt thereof, is anyone of those provided in the Examples, particularly the compoundprovided in one of Examples 12, 25 and 29, or a pharmaceuticallyacceptable salt thereof.

A pharmaceutically acceptable salt of a compound of the instantinvention is an acid-addition salt made from a basic compound of formulaI and an acid which provides a pharmaceutically acceptable anion.

As an additional aspect of the invention there is provided apharmaceutical composition comprising in association with apharmaceutically acceptable carrier, diluent or excipient, a compound offormula I, or a pharmaceutically acceptable salt thereof, as provided inany of the descriptions herein.

Further, there is provided a pharmaceutical composition for treating athromboembolic disorder containing as an active ingredient a compound offormula I, or a pharmaceutically acceptable salt thereof, as provided inany of the descriptions herein.

In addition, there is provided the use of a compound of formula I, or apharmaceutically acceptable salt thereof, as described herein as anactive ingredient in the manufacture of a medicament for use inproducing an anticoagulant or antithrombotic effect.

The present invention also provides a method of inhibiting coagulationin a mammal, particularly a human, comprising administering to a mammalin need of treatment, a coagulation inhibiting dose of a compound offormula I, or a pharmaceutically acceptable salt thereof, having any ofthe definitions herein.

The present invention further provides a method of inhibiting thrombinand/or factor Xa comprising administering to a mammal, particularly ahuman, in need of treatment, a thrombin and/or factor Xa inhibiting doseof compound of formula I having any of the definitions herein.

Further, the present invention provides a method of treating athromboembolic disorder comprising administering to a mammal,particularly a human, in need of treatment, an effective dose of acompound of formula I, or a pharmaceutically acceptable salt thereof,having any of the definitions herein.

Also, there is provided a compound of formula I, or a pharmaceuticallyacceptable salt thereof, having any of the definitions herein for use asan antithrombotic agent.

In addition, there is provided the use of a compound of formula I, or apharmaceutically acceptable salt thereof, having any of the definitionsherein for the manufacture of a medicament for treatment of athromboembolic disorder.

A compound of formula I may be prepared by processes which includeprocesses known in the chemical art for the production of structurallyanalogous compounds or by a novel process described herein. A novelprocess described herein provides another aspect of the invention. Aprocess for the preparation of a compound of formula I (or apharmaceutically acceptable salt thereof) and novel intermediates forthe manufacture of a compound of formula I provide further features ofthe invention and are illustrated by the following procedures in whichthe meanings of the generic radicals are as defined above, unlessotherwise specified. It will be recognized that it may be preferred ornecessary to prepare a compound of formula I in which a functional groupis protected using a conventional protecting group, then to remove theprotecting group to provide the compound of formula I.

Thus, there is provided a process for preparing a compound of formula I,or a pharmaceutically acceptable salt thereof, as provided in any of theabove descriptions, comprising the step selected from

(A) for a compound in which L is carbonyl, acylating an amine of formulaII,

using an acid of formula III (in which R^(a) as hydrogen may be replacedby a nitrogen protecting group R^(p)),

or an activated derivative thereof;

(B) acylating an amine of formula R—NH₂ using an acid of formula IV (inwhich R^(a) as hydrogen may be replaced by a nitrogen protecting groupR^(p)),

or an activated derivative thereof;

(C) for a compound of formula I in which L is methylene, substitutingthe group Y^(a) of a compound of formula VI

in which Y^(a) is a leaving group for nucleophilic aromatic substitutionwith an amine of formula VII

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p)); oralkylating an amine of formula II directly, using a compound of formulaVIII,

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p)) in which Y^(b) is a leaving group for nucleophilicsubstitution, or indirectly, by reductive alkylation using an aldehydeof formula IX;

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p));

(D) for a compound of formula I in which each of R^(a) and R^(b) is(1-3C) normal alkyl, or R^(a) is hydrogen and R^(b) is methyl or(1-3C)alkyl, or NR^(a)R^(b) is 1-pyrrolidinyl or 4-morpholinyl,alkylating a corresponding compound of formula I in which each of R^(a)and R^(b) is hydrogen;

(E) for a compound of formula I in which R^(a) is methyl or (1-3C)normal alkyl, alkylating a corresponding compound of formula I in whichR^(a) is hydrogen;

(F) for a compound of formula I in which R^(b) is formyl, formylating acorresponding compound of formula I in which R^(b) is hydrogen;

(G) alkylating the phenolic oxygen of a compound of formula X,

using a corresponding compound of formula XI (in which R^(a) as hydrogenmay be replaced by a nitrogen protecting group R^(p)),Y—(CH₂)_(i)-Q-(CH₂)_(j)—NR^(a)R^(b)  XIwherein Y is a conventional leaving group for nucleophilic substitutionand wherein, for a compound of formula I in which i is 0, thestereochemistry of the carbon to which Y is attached is inverted fromthat of the product;

(H) for a compound of formula I in which L is carbonyl and R² is—NR^(d)R^(e) or —OR^(f) and L is carbonyl, substitution of the groupY^(c) of a compound of formula XII

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p)), wherein Y^(c) is a leaving group for nucleophilic aromaticsubstitution, using H—NR^(d)R^(e) or H—OR^(f) or the deprotonated formthereof; and

(I) for a compound of formula I in which R² is —OR^(f), alkylating thephenolic oxygen of a compound of formula XIII (in which R^(a) ashydrogen may be replaced by a nitrogen protecting group R^(p)),

using a corresponding compound of formula Y—R^(f) in which Y is aconventional leaving group for nucleophilic substitution;

whereafter, for any of the above procedures, when a functional group isprotected using a protecting group, removing the protecting group;

whereafter, for any of the above procedures, when a pharmaceuticallyacceptable salt of a compound of formula I is required, it is obtainedby reacting the basic form of a basic compound of formula I with an acidaffording a physiologically acceptable counterion or by any otherconventional procedure;

and wherein, unless otherwise specified above in this claim, A³-A⁶, L,R, R¹, R², Q, R^(a)-R^(i), i, j and k have any of the values definedhereinabove.

For a carboxylic acid herein, a typical activated derivative includes anester (particularly a lower alkyl ester such as the methyl or ethylester), an acid halide (particularly the acid chloride), and anactivated ester or anhydride (including the 4-nitrophenyl ester and anactivated ester or anhydride derived from a coupling reagent).

As used herein, a leaving group “Y^(a)” or “Y^(c)” is a moiety which isdisplaced in an aromatic (or heteroaromatic) nucleophilic substitutionreaction, for example a halo group (such as fluoro or chloro), an alkoxygroup (such as methoxy), or a sulfonate ester group (such asmethylsulfonyloxy, p-toluyl-sulfonyloxy or trifluoromethylsulfonyloxy).The substitution may be carried out by heating a mixture of thereagents, for example as described at Example 1-G or Example 3-A,optionally in a polar solvent, and optionally in the presence of a base,such as triethylamine, for example in ethanol in a sealed tube asdescribed at Example 22-E.

As used herein, a leaving group “Y^(b)” is a moiety which is displacedin a nucleophilic substitution reaction, for example a halo group (suchas chloro, bromo or iodo), a sulfonate ester group (such asmethylsulfonyloxy, p-toluyl-sulfonyloxy or trifluoromethylsulfonyloxy),or the reactive species derived from treating an alcohol withtriphenyl-phospine, diethyl azodicarboxylate and triethyl amine (in aMitsunobu reaction).

A preferred method of formylating the nitrogen of a compound in which Rbis hydrogen is the use of a formylating reagent such as formic aceticanhydride.

As used herein, a leaving group “Y” is a moiety which is displaced in anucleophilic substitution reaction, for example a halo group (such asbromo or iodo), a sulfonate ester group (such as methylsulfonyloxy,p-toluylsulfonyloxy or trifluoromethylsulfonyloxy), or the reactivespecies derived from treating an alcohol with triphenylphospine, diethylazodicarboxylate and triethyl amine (in a Mitsunobu reaction). Inaddition, for the preparation of a compound in which Q is —CH(OH)—, thegroup Y—CH₂-Q- may represent an epoxy group. The substitution may becarried out, for example as described at Example 1-F, Example 5-A,Example 6-D, Example 23-F or Example 26-B, as well as at Example 26-A,Example 31-A and Example 32-A.

If not commercially available, a necessary starting material for thepreparation of a compound of formula I may be prepared by a novelprocess described herein or one analogous thereto or by a procedurewhich is selected from standard techniques of organic chemistry,including aromatic and heteroaromatic substitution and transformation,from techniques which are analogous to the syntheses of known,structurally similar compounds, and techniques which are analogous tothe above described procedures or procedures described in the Examples.It will be clear to one skilled in the art that a variety of sequencesis available for the preparation of the starting materials. A novelintermediate or starting material compound provides a further aspect ofthe invention.

Selective methods of substitution, protection and deprotection are wellknown in the art for preparation of a compound such as one of formulaeII-XIII.

Thus, one particular intermediate is an acid of formula III, or a saltthereof, or an activated derivative thereof, (in which R^(a) as hydrogenmay be replaced by a nitrogen protecting group R^(p)),

wherein R¹ and R² have any of the values defined herein above.Conveniently, the salt of a carboxylic acid herein may be the sodium orpotassium salt.

Another aspect is an acid of formula IV (in which R^(a) as hydrogen maybe replaced by a nitrogen protecting group R^(p)),

or an activated derivative thereof, wherein A³-A⁶, L, R¹ and R² have anyof the values defined herein. In addition, for an acid of formula IV, inwhich L is carbonyl, a particular activated derivative is a compound offormula V,

or a salt of the active derivative, in which A³-A⁶, R¹ and R² have anyof the values defined herein, or a derivative thereof in which afunctional group other than the activated derivative of the carboxygroup is protected using a protecting group. Further, for an acid offormula IV, in which L is methylene, a particular activated derivativeis a compound of formula Va,

or a salt of the active derivative, in which A³-A⁶, R¹ and R² have anyof the values defined herein, or a derivative thereof in which afunctional group other than the activated derivative of the carboxygroup is protected using a protecting group.

An additional intermediate, beyond a compound of formula I in which R²is chloro or fluoro, is a compound of formula XII

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p)), wherein Y^(c) is a leaving group for nucleophilic aromaticsubstitution other than fluoro or chloro and A³-A⁶, R and R¹ have any ofthe values defined hereinabove.

A further intermediate is a compound of formula XIII

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p)), wherein A³-A⁶, L, R and R¹ have any of the values definedhereinabove.

As an another aspect of the invention there is provided compound offormula I as disclosed herein but in which R^(a) as hydrogen is replacedby a nitrogen protecting group R^(p), and wherein A³-A⁶, L, R, R¹ andR², otherwise, have any of the values defined herein.

As a further aspect of the invention, there is provided the use of acompound (or activated and/or protected derivative thereof or salt ofthe compound or derivative) of formula III or VI as a starting materialin the preparation of an inhibitor of thrombin and/or factor Xa.

As mentioned above, the invention includes a pharmaceutically acceptablesalt of the thrombin and/or factor Xa inhibiting compound defined by theabove formula I. A basic compound of this invention possesses one ormore functional groups sufficiently basic to react with any of a numberof inorganic and organic acids affording a physiologically acceptablecounterion to form a pharmaceutically acceptable salt.

Generally, a basic compound of the invention is isolated best in theform of an acid addition salt. A salt of a compound of formula I formedwith an acid such as mentioned above is useful as a pharmaceuticallyacceptable salt for administration of the antithrombotic agent and forpreparation of a pharmaceutical composition of the agent. Other acidaddition salts may be prepared and used in the isolation andpurification of the compounds.

As noted above, the optically active isomers and diastereomers of thecompounds of formula I are also considered part of this invention. Suchoptically active isomers may be prepared from their respective opticallyactive precursors by the procedures described above, or by resolving theracemic mixtures. This resolution can be carried out by derivatizationwith a chiral reagent followed by chromatography or by repeatedcrystallization. Removal of the chiral auxiliary by standard methodsaffords substantially optically pure isomers of the compounds of thepresent invention or their precursors.

The compounds of the invention are believed to selectively inhibitthrombin and/or factor Xa over other proteinases and nonenzyme proteinsinvolved in blood coagulation without appreciable interference with thebody's natural clot lysing ability (the compounds have a low inhibitoryeffect on fibrinolysis). Further, such selectivity is believed to permituse with thrombolytic agents without substantial interference withthrombolysis and fibrinolysis.

The invention in one of its aspects provides a method of inhibitingthrombin and/or factor Xa in a mammal comprising administering to amammal in need of treatment an effective (thrombin and/or factor Xainhibiting) dose of a compound of formula I.

In another of its aspects, the invention provides a method of treating athromboembolic disorder comprising administering to a mammal in need oftreatment an effective (thromboembolic disorder therapeutic and/orprophylactic amount) dose of a compound of formula I.

The invention in another of its aspects provides a method of inhibitingcoagulation in a mammal comprising administering to a mammal in need oftreatment an effective (coagulation inhibiting) dose of a compound offormula I.

The thrombin and/or factor Xa inhibition, coagulation inhibition andthromboembolic disorder treatment contemplated by the present methodincludes both medical therapeutic and/or prophylactic treatment asappropriate.

In a further embodiment, the invention relates to treatment, in a humanor animal, of a condition where inhibition of thrombin and/or factor Xais required. The compounds of the invention are expected to be useful inmammals, including man, in treatment or prophylaxis of thrombosis andhypercoagulability in blood and tissues. Disorders in which thecompounds have a potential utility are in treatment or prophylaxis ofthrombosis and hypercoagulability in blood and tissues. Disorders inwhich the compounds have a potential utility, in treatment and/orprophylaxis, include venous thrombosis and pulmonary embolism, arterialthrombosis, such as in myocardial ischemia, myocardial infarction,unstable angina, thrombosis-based stroke and peripheral arterialthrombosis. Further, the compounds have expected utility in thetreatment or prophylaxis of atherosclerotic disorders (diseases) such ascoronary arterial disease, cerebral arterial disease and peripheralarterial disease. Further, the compounds are expected to be usefultogether with thrombolytics in myocardial infarction. Further, thecompounds have expected utility in prophylaxis for reocclusion afterthrombolysis, percutaneous transluminal angioplasty (PTCA) and coronarybypass operations. Further, the compounds have expected utility inprevention of rethrombosis after microsurgery. Further, the compoundsare expected to be useful in anticoagulant treatment in connection withartificial organs, including joint replacement, and cardiac valves.Further, the compounds have expected utility in anticoagulant treatmentin hemodialysis and disseminated intravascular coagulation. Further, thecompounds may be useful in reducing the increased thrombin generationwhich occurs in the airways of patients with asthma; see, E. C. Gabazza,et al., Lung, (1999), 177(4), 253-262. A further expected utility is inrinsing or coating of catheters and mechanical devices used in patientsin vivo, and as an anticoagulant for preservation of blood, plasma andother blood products in vitro. Still further, the compounds haveexpected utility in other diseases where blood coagulation could be afundamental contributing process or a source of secondary pathology,such as cancer, including metastasis, inflammatory diseases, includingarthritis, and diabetes. The anti-coagulant compound is administeredorally or parenterally, e.g. by intravenous infusion (iv), intramuscularinjection (im) or subcutaneously (sc).

The specific dose of a compound administered according to this inventionto obtain therapeutic and/or prophylactic effects will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the compound administered, the rate ofadministration, the route of administration, and the condition beingtreated.

A typical daily dose for each of the above utilities is between about0.01 mg/kg and about 1000 mg/kg. The dose regimen may vary e.g. forprophylactic use a single daily dose may be administered or multipledoses such as 3 or 5 times daily may be appropriate. In critical caresituations a compound of the invention is administered by iv infusion ata rate between about 0.01 mg/kg/h and about 20 mg/kg/h and preferablybetween about 0.1 mg/kg/h and about 5 mg/kg/h.

The method of this invention also is practiced in conjunction with aclot lysing agent e.g. tissue plasminogen activator (t-PA), modifiedt-PA, streptokinase or urokinase. In cases when clot formation hasoccurred and an artery or vein is blocked, either partially or totally,a clot lysing agent is usually employed. A compound of the invention canbe administered prior to or along with the lysing agent or subsequent toits use, and preferably further is administered along with aspirin toprevent the reoccurrence of clot formation.

The method of this invention is also practiced in conjunction with aplatelet glycoprotein receptor (IIb/IIIa) antagonist, that inhibitsplatelet aggregation. A compound of the invention can be administeredprior to or along with the IIb/IIIa antagonist or subsequent to its useto prevent the occurrence or reoccurrence of clot formation.

The method of this invention is also practiced in conjunction withaspirin. A compound of the invention can be administered prior to oralong with aspirin or subsequent to its use to prevent the occurrence orreoccurrence of clot formation. As stated above, preferably a compoundof the present invention is administered in conjunction with a clotlysing agent and aspirin.

This invention also provides a pharmaceutical composition for use in theabove described therapeutic method. A pharmaceutical composition of theinvention comprises a compound of formula I, or a pharmaceuticallyacceptable salt thereof, in association with a pharmaceuticallyacceptable carrier, diluent or excipient.

The active ingredient in such formulations comprises from 0.1 percent to99.9 percent by weight of the formulation. By “pharmaceuticallyacceptable” it is meant the carrier, diluent or excipient must becompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The present pharmaceutical compositions are prepared by known proceduresusing well known and readily available ingredients. The compositions ofthis invention may be formulated so as to provide quick, sustained, ordelayed release of the active ingredient after administration to thepatient by employing procedures well known in the art.

The ability of a compound of the present invention to be an effectiveand orally active thrombin and/or factor Xa inhibitor may be evaluatedin one or more of the following assays or in other standard assays knownto those in the art.

The inhibition by a compound of the invention of a serine protease ofthe human blood coagulation system or of the fibrinolytic system, aswell as of trypsin, is determined in vitro for the particular enzyme bymeasuring its inhibitor binding affinity in an assay in which the enzymehydrolyzes a particular chromogenic substrate, for example as describedin Smith, G. F.; Gifford-Moore, D.; Craft, T. J.; Chirgad{grave over(z)}e, N.; Ruterbories, K. J.; Lindstrom, T. D.; Satterwhite, J. H.Efegatran: A New Cardiovascular Anticoagulant. New Anticoagulants forthe Cardiovascular Patient; Pifarre, R., Ed.; Hanley & Belfus, Inc.:Philadelphia, 1997; pp. 265-300. The inhibitor binding affinity ismeasured as apparent association constant Kass which is the hypotheticalequilibrium constant for the reaction between enzyme and the testinhibitor compound (I).

Conveniently, enzyme inhibition kinetics are performed in a high-volumeprotocol using automated dilutions of inhibitors (n=3 for each of fourto eight inhibitor concentrations) into 96-well polystyrene plates andreaction rates are determined from the rate of hydrolysis of appropriatep-nitroanilide substrates at 405 nm using a Thermomax plate reader fromMolecular Devices (San Francisco, Calif.). The same general protocol isfollowed for all enzymes studied: In each well is placed 50 μL buffer(0.06 M Tris, 0.3 M NaCl, pH 7.4), followed by 25 μL of inhibitorsolution (in 100% methanol) and 25 μL enzyme solution (e.g., humanfactor Xa, 32 nM in 0.03 M Tris, 0.15 M NaCl, 1 mg/mL HAS); finally,within two minutes, 150 μL aqueous solution of chromogenic substrate(e.g., 0.3 mM BzIle-Glu-Gly-Arg-pNA) is added to start the enzymaticreaction. Final factor Xa concentration is 3.2 nM. The rates ofchromogenic substrate hydrolysis reactions provide a linear relationshipwith the enzymes studied such that free enzyme can be quantitated inreaction mixtures. Data is analyzed directly as rates by the Softmaxprogram to produce [free enzyme] calculations for tight-binding Kassdeterminations. For apparent Kass determinations, human factor Xa isused to hydrolyze BzIle-Glu-Gly-Arg-pNA; 5.9 nM human thrombin is usedto hydrolyze 0.2 mM BzPhe-Val-Arg-pNA; 3.4 nM human plasmin is used with0.5 mM HD-Val-Leu-Lys-pNA; 1.2 nM human nt-PA is used with 0.8 mMHD-Ile-Pro-Arg-pNA; and 0.4 nM urokinase is used with 0.4 mMpyro-Glu-Gly-Arg-pNA.

Kass is calculated for a range of concentrations of test compounds whichproduce hydrolysis inhibition of between 20% and 80% of control and themean value reported in units of liter per mole. In general, a compoundof formula I of the instant invention, as exemplified hereinbelow in theworking examples, exhibits a Kass for factor Xa of 0.1-1,000×10⁶ L/moleor greater. Most of the examples also exhibit a Kass for thrombin(factor IIa) of 0.3-100×10⁶ L/mole or greater. Examples in which L iscarbonyl and R, R¹ and R² are the preferred values described aboveexhibit a Kass for factor Xa of 40×10⁶ L/mole or greater and a Kass forthrombin (factor IIa) of 4×10⁶ L/mole or greater.

The thrombin and/or factor Xa inhibitor preferably should sparefibrinolysis induced by urokinase, tissue plasminogen activator (t-PA)and streptokinase. This would be important to the therapeutic use ofsuch an agent as an adjunct to streptokinase, tp-PA or urokinasethrombolytic therapy and to the use of such an agent as an endogenousfibrinolysis-sparing (with respect to t-PA and urokinase) antithromboticagent. In addition to the lack of interference with the amidase activityof the fibrinolytic proteases, such fibrinolytic system sparing can bestudied by the use of human plasma clots and their lysis by therespective fibrinolytic plasminogen activators.

Materials

Dog plasma is obtained from conscious mixed-breed hounds (either sexButler Farms, Clyde, N.Y., U.S.A.) by venipuncture into 3.8 percentcitrate. Fibrinogen is prepared from fresh dog plasma and humanfibrinogen is prepared from in-date ACD human blood at the fraction I-2according to previous procedures and specification. Smith, Biochem. J.,185, 1-11 (1980; and Smith, et al., Biochemistry, 11, 2958-2967, (1972).Human fibrinogen (98 percent pure/plasmin free) is from AmericanDiagnostica, Greenwich, Conn. Radiolabeling of fibrinogen 1-2preparations is performed as previously reported. Smith, et al.,Biochemistry, 11, 2958-2967, (1972). Urokinase is purchased from LeoPharmaceuticals, Denmark, as 2200 Ploug units/vial. Streptokinase ispurchased from Hoechst-Roussel Pharmaceuticals, Somerville, N.J.

Anticoagulant Activity

Materials

Dog plasma and rat plasma are obtained from conscious mixed-breed hounds(either sex, Butler Farms, Clyde, N.Y., U.S.A.) or from anesthetizedmale Sprague-Dawley rats (Harlan Sprague-Dawley, Inc., Indianapolis,Ind., U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen isprepared from in-date ACD human blood as the fraction 1-2 according toprevious procedures and specifications. Smith, Biochem. J., 185, 1-11(1980); and Smith, et al., Biochemistry, 11, 2958-2967 (1972). Humanfibrinogen is also purchased as 98 percent pure/plasmin free fromAmerican Diagnostica, Greenwich, Connecticut. Cbagulation reagentsActin, Thromboplastin, Innovin and Human plasma are from BaxterHealthcare Corp., Dade Division, Miami, Fla. Bovine thrombin fromParke-Davis (Detroit, Mich.) is used for coagulation assays in plasma.

Methods

Anticoagulation Determinations

Coagulation assay procedures are as previously described. Smith, et al.,Thrombosis Research, 50, 163-174 (1988). A CoAScreener coagulationinstrument (American LABor, Inc.) is used for all coagulation assaymeasurements. The prothrombin time (PT) is measured by adding 0.05 mLsaline and 0.05 mL Thromboplastin-C reagent or recombinant human tissuefactor reagent (Innovin) to 0.05 mL test plasma. The activated partialthromboplastin time (APTT) is measured by incubation of 0.05 mL testplasma with 0.05 mL Actin reagent for 120 seconds followed by 0.05 mLCaCl₂ (0.02 M). The thrombin time (TT) is measured by adding 0.05 mLsaline and 0.05 mL thrombin (10 NIH units/mL) to 0.05 mL test plasma.Thus, the plasma concentrations are three times the assayconcentrations. The compounds of formula I are added to human or animalplasma over a wide range of concentrations to determine prolongationeffects on the APTT, PT, and TT assays. Linear extrapolations areperformed to estimate the concentrations required to double the clottingtime for each assay. Compounds of the instant invention potentlyextended the prolongation times in the APTT and PT assays, for examplein some cases, with assay concentrations necessary to double the APPT orPT of less than 1 μM.

Animals

Male Sprague Dawley rats (350-425 gm, Harlan Sprague Dawley Inc.,Indianapolis, Ind.) are anesthetized with xylazine (20 mg/kg, s.c.) andketamine (120 mg/kg, s.c.) or preferably are anesthetized usingisoflurane anesthesia (2-3%, conveniently 2.5%, for surgery; 1.5-2.5%,conveniently 2.5%, for maintenance; flow rate kept at 0.5% throughout)and maintained on a heated water blanket (37° C.). The jugular vein(s)is cannulated to allow for infusions.

Arterio-Venous Shunt Model

The left jugular vein and right carotid artery are cannulated with 20 cmlengths of polyethylene PE 60 tubing. A 6 cm center section of largertubing (PE 190) with a cotton thread (5 cm) in the lumen, is frictionfitted between the longer sections to complete the arterio-venous shuntcircuit. Blood is circulated through the shunt for 15 min before thethread is carefully removed and weighed. The weight of a wet thread issubtracted from the total weight of the thread and thrombus (see J. R.Smith, Br J Pharmacol, 77:29, 1982).

FeCl₃ Model of Arterial Injury

The carotid arteries are isolated via a midline ventral cervicalincision. A thermocouple is placed under each artery and vesseltemperature is recorded continuously on a strip chart recorder. A cuffof tubing (0.058 ID×0.077 OD×4 mm, Baxter Med. Grade Silicone), cutlongitudinally, is placed around each carotid directly above thethermocouple. FeCl₃ hexahydrate is dissolved in water and theconcentration (20 percent) is expressed in terms of the actual weight ofFeCl₃ only. To injure the artery and induce thrombosis, 2.85 μL ispipetted into the cuff to bathe the artery above the thermocouple probe.Arterial occlusion is indicated by a rapid drop in temperature. The timeto occlusion is reported in minutes and represents the elapsed timebetween application of FeCl₃ and the rapid drop in vessel temperature(see K. D. Kurz, Thromb. Res., 60:269, 1990).

Ex Vivo Coagulation Parameters

Ex vivo plasma thrombin time (TT), prothrombin time (PT) and activatedpartial thromboplastin time (APTT) are measured with a fibrometer. Bloodis sampled from a jugular catheter and collected in syringe containingsodium citrate (3.8 percent, 1 part to 9 parts blood). To measure TT,rat plasma (0.1 mL) is mixed with isotonic saline (0.1 mL) and bovinethrombin (0.1 mL, 30 U/mL in TRIS buffer; Parke Davis) at 37° C. For PT,to plasma (0.1 mL) mixed with isotonic saline (0.1 mL) is added PTreagent (0.1 mL, Dade, Thromboplastin-C); and the fibrometer startedimmediately after the addition of the final reagent. For APTT, plasma(0.1 mL) and APTT solution (0.1 mL, Organon Teknika) are incubated for 5minutes (37° C.); and CaCl₂ (0.1 mL, 0.025 M) is added to startcoagulation. Assays are done in duplicate and averaged.

Index of Bioavailability

Bioavailability studies may be conducted as follows. Compounds areadministered as aqueous solutions, or as solutions in 5% PEG 200, tomale Fisher rats, intravenously (iv) at 5 mg/kg via tail vein injectionand orally (po) as aqueous solutions, or as a suspension in 5% acacia,to fasted animals at 20 mg/kg by gavage. Serial blood samples areobtained at 5, 30, 120, and 240 minutes postdose following intravenousadministration and at 1, 2, 4, and 6 hours after oral dosing. Plasma isanalyzed for drug concentration using an HPLC procedure involving C8Bond Elute (Varian) cartridges for sample preparation and a methanol/30nM ammonium acetate buffer (pH 4) gradient optimized for each compound.% Oral bioavailability is calculated by the following equation:${\%\quad{Oral}\quad{bioavailability}} = {\frac{{AUC}\quad{po}}{{AUC}\quad{iv}} \times \frac{{Dose}\quad{iv}}{{Dose}\quad{po}} \times 100}$where AUC is area under the curve calculated from the plasma level ofcompound over the time course of the experiment following oral (AUC po)and intravenous (AUC iv) dosing.Compounds

For oral determinations, the compound may be administered orally, bygavage, as a suspension in 5% acaia to conscious fasted rats. Thepretreatment time before flow is established through the shunt isselected based upon the peak apparent plasma concentration recorded inpreliminary time course experiments that track apparent drugconcentration in plasma following oral administration to consciousfasted rats, and typically varies between 1 to 5 hours. Animals used inantithrombotic efficacy experiments are anesthetized as described 15minutes before the predetermined pretreatment time to allow for surgicalpreparation of the animals. Compound solutions are prepared fresh dailyin normal saline or in 5% PEG200 in water for iv determinations and areinjected as a bolus or are infused starting 15 minutes before andcontinuing throughout the experimental perturbation which is 15 minutesin the arteriovenous shunt model and 60 minutes in the FeCl₃ model ofarterial injury and in the spontaneous thrombolysis model. Typically,bolus injection volume is 1 mL/kg for iv, and 5 mL/kg for po, andinfusion volume is 3 mL/h. For a similar procedure run in theanesthesized rabbit, for example an infusion rate of 6.8 mL/h was usedfor one compound infused in 5% PEG200 in water.

Statistics

Results are expressed as means +/−SEM. One-way analysis of variance isused to detect statistically significant differences and then Dunnett'stest is applied to determine which means are different. Significancelevel for rejection of the null hypothesis of equal means is P<0.05.

Animals

Male dogs (Beagles; 18 months-2 years; 12-13 kg, Marshall Farms, NorthRose, New York 14516) are fasted overnight and fed Purina certifiedPrescription Diet (Purina Mills, St. Louis, Mo.) 240 minutes afterdosing. Water is available ad libitum. The room temperature ismaintained between 66-74° F.; 45-50 percent relative humidity; andlighted from 0600-1800 hours.

Pharmacokinetic Model.

Test compound is formulated immediately prior to dosing by making asuspension in a “wet granulaion” (povidone, 0.85 mg/mL; lactose, 15.0mg/mL; and polysorbate 80, 65 μL in 250 mL water). Dogs are given asingle 20 mg/kg (in 25 mL of wet granulation) dose of test compound byoral gavage. Blood samples (4.5 mL) are taken from the cephalic vein at0.25, 0.5, 0.75, 1, 2, 3, 4 and 6 hours after dosing. Samples arecollected in citrated Vacutainer tubes and kept on ice prior toreduction to plasma by centrifugation. Plasma samples are analyzed byHPLC MS. Plasma concentration of test compound is recorded and used tocalculate the pharmacokinetic parameters: elimination rate constant, Ke;total clearance, Clt; volume of distribution, V_(D); time of maximumplasma test compound concentration, Tmax; maximum concentration of testcompound of Tmax, Cmax; plasma half-life, t0.5; and area under thecurve, A.U.C.; fraction of test compound absorbed, F.

Canine Model of Coronary Artery Thrombosis

Male dogs (Beagles, as described above) are fasted overnight and dosedwith test compound that is fomulated immediately prior to'dosing bymaking a suspension in a “wet granulation” as described above. Dogs aregiven a single dose of 5, 10 or 20 mg/kg (in 25 mL of wet granulation)of test compound by oral gavage. Based on the pharmacokinetics of thetest compound, dogs are dosed either 1 or 2 hours prior to anesthesia.Dogs are anesthetized with sodium pentobarbital (30 mg/kg intravenously,i.v.), intubated, and ventilated with room air. Tidal volume andrespiratory rates are adjusted to maintain blood PO₂, PCO₂, and pHwithin normal limits. Subdermal needle electrodes are inserted for therecording of a lead II ECG.

The left jugular vein and common carotid artery are isolated through aleft mediolateral neck incision. Arterial blood pressure (ABP) ismeasured continuously with a precalibrated Millar transducer (modelMPC-500, Millar Instruments, Houston, Tex., U.S.A.) inserted into thecarotid artery. The jugular vein is cannulated for blood sampling duringthe experiment. In addition, the femoral veins of both hindlegs arecannulated for administration of test compound.

A left thoracotomy is performed at the fifth intercostal space, and theheart is suspended in a pericardial cradle. A 1- to 2-cm segment of theleft circumflex coronary artery (LCX) is isolated proximal to the firstmajor diagonal ventricular branch. A 26-gauge needle-tipped wire anodalelectrode (Teflon-coated, 30-gauge silverplated copper wire) 3-4 mm longis inserted into the LCX and placed in contact with the intimal surfaceof the artery (confirmed at the end of the experiment). The stimulatingcircuit is completed by placing the cathode in a subcutaneous (s.c.)site. An adjustable plastic occluder is placed around the LCX, over theregion of the electrode. A precalibrated electromagnetic flow probe(Carolina Medical Electronics, King, N.C., U.S.A.) is placed around theLCX proximal to the anode for measurement of coronary blood flow (CBF).The occluder is adjusted to produce a 40-50 percent inhibition of thehyperemic blood flow response observed after 10-s mechanical occlusionof the LCX. All hemodynamic and ECG measurements are recorded andanalyzed with a data acquisition system (Notochord HEM data analysissystem, Croissy, France).

Thrombus Formation and Compound Administration Regimens

Electrolytic injury of the intima of the LCX is produced by applying100-μA direct current (DC) to the anode. The current is maintained for60 min and then discontinued whether the vessel has occluded or not.Thrombus formation proceeds spontaneously until the LCX is totallyoccluded (determined as zero CBF and an increase in the S-T segment fora minimum of 30 minutes). The preparation is followed for 4 hours atwhich time the animal is euthanized and the thrombus is dissected fromthe LCX and weighed.

Hematology, Coagulation and Template Bleeding Time Determinations

Citrated blood (3 mL, 1 part 3.8% citrate: 9 parts blood) is drawnbefore drug administration, at 60 min after administration, at 60 minafter initiation of vessel injury and just prior to the end of theexperiment. Whole blood cell counts, hemoglobin, and hematocrit valuesare determined on a 40-μL sample of the citrated whole blood with ahematology analyzer (Cell-Dyn 900, Sequoia-Turner, Mount View, Calif.,U.S.A.). The remaining blood was cetrifuged at 3,000 g for 5 min toprepare cell-free plasma. Plasma clotting times, prothrombin time (PT)and activated partial thromoplastin times (APTT) were performed usingstandard Dade reagents and the Coa-Screener coagulation device (AmericanLabor, Largo, Fla.). Gingival template bleeding times are determinedwith a Simplate II bleeding time device (Organon Teknika Durham, N.C.,U.S.A.). The device is used to make 2 horizontal incisions in thegingiva of either the upper or lower left jaw of the dog. Each incisionis 3 mm wide×2 mm deep. The incisions are made, and a stopwatch is usedto determine how long bleeding occurs. A cotton swab is used to soak upthe blood as it oozes from the incision. Template bleeding time is thetime from incision to stoppage of bleeding. Bleeding times are takenjust before administration of test compound (0 min), 60 min intoinfusion, at conclusion of administration of the test compound (120min), and at the end of the experiment.

All data are analyzed by one-way analysis of variance (ANOVA) followedby Dunnet's post hoc t test to determine the level of significance.Repeated-measures ANOVA are used to determine significant differencesbetween time points during the experiments. Values are determined to bestatistically different at least at the level of p<0.05. All values aremean±SEM. All studies are conducted in accordance with the guidingprinciples of the American Physiological Society. Further detailsregarding the procedures are described in Jackson, et al., J.Cardiovasc. Pharmacol., (1993), 21, 587-599.

Compounds of the instant invention are potent anticoagulant andantithrombotic agents which exhibit particularly good plasma exposurefollowing oral administration, as well as desirable volume ofdistribution and tissue selectivity properties, as evidenced by standardpharmacokinetic/pharmcodynamic and brain flux assays.

The following Examples are provided to further describe the inventionand are not to be construed as limitations thereof.

The abbreviations, symbols and terms used in the examples andpreparations have the following meanings.

-   -   Ac=acetyl    -   Analysis=elemental analysis    -   aq=aqueous    -   Boc=t-butyloxycarbonyl    -   t-Bu=tert-butyl    -   Calcd=calculated    -   conc=concentrated    -   DMF=dimethylformamide    -   DMSO=dimethylsulfoxide    -   EtOAc=ethyl acetate    -   HOAc=acetic acid    -   EtOH=ethanol    -   MeOH=methanol    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   HPLC=High Performance Liquid Chromatography    -   IR=Infrared Spectrum    -   ¹NMR=(proton) nuclear magnetic resonance spectrum    -   ES-MS=electron spray mass spectrum    -   IS-MS=ion spray mass spectrum    -   FD-MS=field desorption mass spectrum

When indicated without data, ¹NMR, IR or MS means a satisfactoryspectrum was obtained.

EXAMPLE 1 Preparation ofN-(4-Chlorophenyl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxamide

A. 3-tert-Butoxycarbonylaminopyridine

3-Aminopyridine (4.29 g, 45.6 mmol) was dissolved in THF (100 mL). A 1 MTHF solution of sodium hexamethyl-disilazide (NaHMDS, 100 mL, 100 mmol)was added dropwise via an addition funnel. After 15 min, a solution ofdi-t-butyl dicarbonate [(Boc)₂O] (11.92 g, 54.6 mmol) in THF (100 mL)was added dropwise. After 15 min, the reaction was quenched with water(100 mL) and extracted with EtOAc (500 mL). The organic layer was washedwith water (2×100 mL). The aqueous layers were combined and extractedwith EtOAc (200 mL). The organic layers were combined, dried over sodiumsulfate, filtered, and concentrated. The crude material was purified byflash column chromatography (30% EtOAc/CH₂Cl₂) to give the desiredproduct (5.195 g, 30.5 mmol, 67%) as an orange solid.

¹NMR (400 MHz, DMSO-d₆): δ 9.53(s, 1H); 8.57(s, 1H); 8.14(d, J=4.4 Hz,1H); 7.84(d, J=8.0 Hz, 1H); 7.25(m, 1H); 1.44(s, 9H).

IS-MS, m/e 195.3 (m+1).

Analysis for C₁₀H₁₄N₂O₂:

Calcd: C, 61.84; H, 7.27; N, 14.42;

Found: C, 61.94; H, 7.18; N, 14.38.

B.3-(N-tert-Butoxycarbonylamino)-N-(4-chlorophenyl)-pyridine-4-carboxamide

The 3-tert-butoxycarbonylaminopyridine (2.0035 g, 10.32 mmol) wasdissolved in THF (100 mL). The solution was cooled to −30° C. in a dryice/acetonitrile bath, then t-BuLi (13 mL, 22.1 mmol) was addeddropwise. After 1 h, 4-chlorophenyl isocyanate (1.911 g, 12.44 mmol) wasadded. The reaction mixture was warmed to 0° C. After 1.5 h, thereaction was warmed to room temperature. After 3 h at room temperature,the reaction was quenched with water (100 mL) and extracted with EtOAc(800 mL). The organic layer was washed with water (2×50 mL), dried oversodium sulfate, filtered, and concentrated. The crude material waspurified by flash column chromatography (350 g silica, 30%EtOAc/-CH₂Cl₂) to give the amide (1.284 g, 3.69 mmol, 36%) as a paleyellow solid.

¹NMR (400 MHz, DMSO-d₆): δ 10.61(s, 1H); 9.48(s, 1H); 8.93(s, 1H);8.39(d, J=5.2 Hz, 1H); 7.71(d, J=8.8 Hz, 1H); 7.59(d, J=5.2 Hz, 1H);7.39(d, J=9.2 Hz, 2H); 1.37(s, 9H).

IS-MS, m/e 348.2 (m+1).

C. 3-Amino-N-(4-chlorophenyl)pyridine-4-carboxamide

To3-(N-tert-butoxycarbonylamino)-N-(4-chlorophenyl)-pyridine-4-carboxamide(552 mg, 1.59 mmol) was added trifluoroacetic acid (3 mL, 38.95 mmol).After stirring for 10 min, the reaction mixture was concentrated,diluted with CH₂Cl₂, washed with satd Na₂CO₃, dried (Na₂SO₄) andconcentrated to give the title compound (367 mg, 93%) as a pale yellowsolid.

¹NMR (300 MHz, DMSO-d₆): δ 10.31(s, 1H); 8.14(s, 1H); 7.78(d, J=6.8 Hz,1H); 7.71(d, J=12.0 Hz, 2H); 7.46(d, J=6.8 Hz, 1H); 7.37(d, J=12.0 Hz,2H); 6.34(s, 2H).

IS-MS, m/e 248.3 (m+1).

Analysis for C₁₂H₁₀ClN₃O:

Calc: C, 58.19; H, 4.07; N, 16.97;

Found: C, 58.30; H, 4.30; N, 16.80.

D. 1-Boc-4-hydroxypiperidine

To a mixture of 4-hydroxypiperidine (60.69 g, 0.6 mol),4-(dimethylamino)pyridine (74 mg, 0.6 mmol), CH₂Cl₂ (150 mL), and THF(150 mL) was added di-t-butyl dicarbonate [(Boc)₂O] (130.95 g, 0.6 mol).After stirring for 6 h, the reaction mixture was heated to 35° C. for 16h. More (Boc)₂O (13.09 g, 0.06 mol) in THP (20 mL) was added, and themixture was heated for 10 h. After cooling, water and ether (1 L) wereadded and the mixture was stirred for 2 h. The organic layer waspartitioned, dried (MgSO₄), and concentrated in vacuo. The residue wascrystallized from ether to give the product as a white solid (105 g,87%).

¹NMR (300 MHz, DMSO-d₆): δ 3.85 (m, 3H), 3.04 (m, 2H), 1.88 (m, 2H),1.56 (m, 2H), 1.25 (s, 9H).

IS-MS, m/e: 202.0 (m+1).

E. Methyl 4-Fluoro-2-hydroxybenzoate

i. 4-Fluoro-2-hydroxybenzoic Acid

Potassium carbonate (51.6 g, 373 mmol) was dried by heating at 200° C.for 12 h. This was treated with 3-fluorophenol (16.5 g, 147 mmol) in asealed container which was then pressurized with carbon monoxide to 61.2bar (900 psig). The reaction mixture was heated to 175° C. for 5 h.Subsequently, the reaction mixture was dissolved in water, acidifiedwith concentrated hydrochloric acid, and filtered. The solid was washedwith water, then hexanes. The solid was then dissolved in EtOAc, driedover magnesium sulfate, and concentrated to give 12 g of solid. Thiscrude solid was purified by flash chromatography using, CHCl₃/MeOH/HOAc(98/1/1) to give 11 g of a white solid which was recrystallized fromtoluene to give the title compound (9.5 g, 41%) as needle solids.

¹NMR

FD-MS, m/e 155 (m−1)

Analysis for C₇H₅FO₃.0.1 C₇H₈.0.3 H₂O:

Calcd: C, 54.17; H, 3.78;

Found: C, 54.12; H, 3.39.

ii. Methyl 4-Fluoro-2-hydroxybenzoate

A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) inbenzene (100 mL) and MeOH (20 mL) was cooled in an ice bath and a 2 Mhexane solution of (trimethyl-silyl)diazomethane (50 mL) was addeddropwise. The reaction was stirred overnight at ambient temperature,diluted with benzene (348 mL) and MeOH (39 mL), and treated with more ofthe (trimethylsilyl)diazomethane solution (15 mL). The mixture wasconcentrated in vacuo to dryness to give the title compound (10.4 g,98%) as a solid.

¹NMR

FD-MS, m/e 170 (m+)

Analysis for C₈H₇FO₃:

Calcd: C, 56.48; H, 4.15;

Found: C, 56.17; H, 4.28.

F. Methyl 2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate

A mixture of methyl 4-fluoro-2-hydroxybenzoate (5.1 g, 30 mmol),triphenylphosphine (9.5 g, 36 mmol),1-tert-butoxycarbonyl-4-hydroxypiperidine (6 g, 30 mmol), and benzene(10 mL) was heated until all solids dissolved. The solution was cooledto 0° C., then sonicated while adding diethyl azodicarboxylate (6.3 g,36 mmol) dropwise. After the addition was complete, the reaction mixturewas sonicated for an additional 60 min, diluted with CH₂Cl₂ (25 mL), andpurified by flash chromatography, eluting with 10% EtOAc in hexanes toyield the title compound (6.45 g, 61%) as a white solid.

¹NMR

IS-MS, m/e 354 (m+1)

Analysis for C₁₈H₂₄FNO₅:

Calcd: C; 61.18; H, 6.85; N, 3.98;

Found: C, 60.98; H, 6.86; N, 4.04.

G. Methyl2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoate

The methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate(7.99 mmol, 22.6 mmol) was diluted with pyrrolidine (18 mL, 215.6 mmol).The resulting mixture was heated to 80° C. After 3 h, the reactionmixture was cooled to room temperature and quenched with water (50 mL).The mixture was extracted with dichloromethane (200 mL). The organiclayer was washed with saturated aqueous citric acid (3×50 mL), driedover sodium sulfate, filtered, and concentrated to give the titlecompound (9.14 g, 100%) as a colorless oil.

¹NMR (400 MHz, DMSO-d₆): δ 7.59(d, J=9.2 Hz, 1H); 6.14(dd, J=2.2, 8.6Hz, 1H); 6.09(s, 1H); 4.67(m, 1H); 3.65(s, 3H); 3.44-3.23(m, 8H);1.91(s, 4H); 1.74(m, 2H); 1.64(m, 2H); 1.37 (s, 9H).

IS-MS, m/e 405.5 (m+1).

Analysis for C₂₂H₃₂N₂O₅:

Calcd: C, 65.32; H, 7.97; N, 6.93;

Found: C, 65.62; H, 8.00; N, 7.14.

H. 2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoicAcid

A mixture of methyl2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoate(9.133 g, 22.6 mmol), 1 M LiOH (40 mL, 40 mmol), MeOH (30 mL) and THF(90 mL) was heated at 60° C. for 14 h. The reaction mixture wasconcentrated to one-third of its initial volume, diluted with EtOAc (700mL), and washed with satd citric acid (3×50 mL), and water (3×50 mL)before it was dried (Na₂SO₄), filtered, and concentrated to give thetitle compound (6.90 g, 78%) as a white solid.

¹NMR (400 MHz, DMSO-d₆): δ 11.47(brs, 1H); 7.56(d, J=8.8 Hz, 1H);6.11(d, J=8.4 Hz, 1H); 6.05(s, 1H); 4.64(m, 1H); 3.44-3.11(m, 8H);1.88(m, 4H); 1.72(m, 2H); 1.60(m, 2H); 1.33(s, 9H).

IS-MS, m/e 391.3 (m+1).

Analysis for C₂₁H₃₀N₂O₅:

Calc: C, 64.60; H, 7.74; N, 7.17;

Found: C, 67.23; H, 8.13; N, 7.65.

I.3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(4-chlorophenyl)pyridine-4-carboxamide

To a mixture of2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoic(566 mg, 1.45 mmol), pyridine (0.15 mL, 1.85 mmol), DMF (3 drops), andCH₂Cl₂ (15 mL) was added oxalyl chloride (0.15 mL, 1.72 mmol) and themixture was stirred for 1.5 h. The resulting2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylchloride was concentrated and was diluted with CH₂Cl₂ (20 mL). To thismixture was added pyridine (0.15 mL, 1.85 mmol), followed by solid3-amino-N-(4-chlorophenyl)pyridine-4-carboxamide (326 mg, 1.32 mmol).The reaction mixture was stirred for 16 h, diluted with CH₂Cl₂ (100 mL),washed with satd NaHCO₃ (2×10 mL), dried (Na₂SO₄), and concentrated. Theresulting residue was chromatographed over silica gel (80 g; CH₂Cl₂ to3% MeOH/CH₂Cl₂) to give the title compound (406 mg, 50%) as an off-whitesolid.

¹NMR (300 MHz, DMSO-d₆): δ 10.81(s, 1H); 10.63 (s, 1H); 9.47(s, 1H);8.42(d, J=5.1 Hz, 1H); 7.76(m, 3H); 7.65(d, J=4.8 Hz, 1H); 7.39(d, J=8.7Hz, 2H); 6.22(d, J=9.0 Hz, 1H); 6.15(s, 1H); 4.79(m, 1H); 3.74(d, J=13.2HZ, 2H); 3.29(m, 4H); 2.98(m, 2H); 1.92(m, 8H); 1.34(s, 9H).

FD-MS, m/e 619 (m).

Analysis for C₃₃H₃₈ClN₅O₅:

Calc: C, 63.91; H, 6.18; N, 11.29;

Found: C, 64.12; H, 6.25; N, 11.13.

J.N-(4-Chlorophenyl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxamide

Using a procedure equivalent to Example 1-C,3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(4-chlorophenyl)pyridine-4-carboxamidegave the title compound (132 mg, 85%) as a yellow solid.

¹NMR (400 MHz, DMSO-d₆): δ 9.52(s, 1H); 8.42(d, J=5.2 Hz, 1H); 7.76(m,3H); 7.64(d, J=4.8 Hz, 1H); 7.40(d, J=9.2 Hz, 2H); 6.23(d, J=6.4 Hz,1H); 6.13(s, 1H); 4.63(m, 1H); 3.28(m, 4H); 2.79(m, 2H); 2.49(m, 2H);1.88(m, 6H); 1.65(m, 2H).

IS-MS, m/e 520.3 (m+1).

Analysis for C₂₈H₃₀ClN₅O₃:

Calc: C, 64.57; H, 5.81; N, 13.47;

Found: C, 64.56; H, 5.79; N, 13.34.

EXAMPLE 2 Preparation ofN-(5-Chloropyridin-2-yl)-3-[4-fluoro-2-(piperidin-4-yloxy)benzoylamino)]pyridine-2-carboxamideTrifluoroacetate

A. N-(5-Chloropyridin-2-yl)-3-aminopyridine-2-carboxamide

A medium pressure reaction apparatus was charged with3-amino-2-chloropyridine (500 mg, 3.89 mmol), 2-amino-5-chloropyridine(1.00 g, 7.78 mmol), palladium acetate (88 mg, 0.39 mmol),1,3-bis(diphenylphosphino)propane (483 mg, 1.17 mmol) and triethylamine(590 mg, 5.84 mmol). The mixture was placed under a carbon monoxideatmosphere at 4.1 bar (60 psig) and heated at 100° C. After 72 h, themixture was filtered, concentrated and the residue purified by columnchromatography (SiO₂: 0 to 5% EtOAc in methylene chloride) affording 550mg (57%) of the title compound.

¹NMR, IR

IS-MS, m/e 249 (m+1)

Analysis for C₁₁H₉ClN₄O:

Calcd: C, 53.13; H, 3.65; N, 22.53;

Found: C, 53.40; H, 3.66; N, 22.45.

B. 2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-fluoro-benzoic Acid

A mixture of methyl2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate (3.05 g,8.64 mmol), 1 M aq LiOH (15 mL, 15 mmol), MeOH (15 mL), and THF (45 mL)was stirred overnight. The reaction mixture was diluted with EtOAc,washed with satd citric acid, dried over MgSO₄, concentrated, andtriturated with ether to give the acid as a white solid (2.23 g, 76%).

¹NMR (300 MHz, CDCl₃): δ 7.68 (m, 1H), 7.10 (d, J=8.7 Hz, 1H), 6.79 (m,1H), 4.72 (m, 1H), 3.48 (m, 4H), 1.65 (m, 2H), 1.60 (m, 2H), 1.37 (s,9H).

IS-MS, m/e: 340(m+1).

C.N-(5-Chloropyridin-2-yl)-3-[4-fluoro-2-(piperidin-4-yloxy)benzoylamino]pyridine-2-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example1-I, 3-amino-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide (347 mg,1.40 mmol) and2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoic acid (500 mg,1.47 mmol) yielded, after deprotection of the coupled product usingmethods substantially equivalent to those described in Example 1-J, 250mg (38%) of the title compound.

¹NMR, IR

IS-MS, m/e=470 (m+1)

Analysis for C₂₈H₂₉ClFN₅O₅.H₂O.6 CF₃CO₂H:

Calcd: C, 35.86; H, 2.49; N, 5.97;

Found: C, 35.67; H, 2.65; N, 6.57.

EXAMPLE 3 Preparation ofN-(5-Chloropyridin-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-2-carboxamideTrifluoroacetate

A.3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide

Using methods substantially equivalent to those described in Example1-G,3-[4-fluoro-2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(100 mg, 0.18 mmol) and pyrrolidine (5.0 mL) yielded, after purificationby flash chromatography (SiO₂: methylene chloride), 112 mg (99%) of thetitle compound.

¹NMR, IR

IS-MS, m/e=621.5 (m+1)

B.N-(5-Chloropyridin-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-2-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example1-C, 3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (100 mg,0.16 mmol) yielded, after purification by flash chromatography (SiO₂: 5%to 20% methanol in methylene chloride), 25 mg (30%) of the titlecompound.

¹NMR, IR

IS-MS, m/e=521.32 (m+1)

EXAMPLE 4 Preparation ofN-(5-Chloropyridin-2-yl)-3-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)benzoylamino]pyridine-2-carboxamideTrifluoroacetate

A.3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide

Using methods substantially equivalent to those described in Example1-G,3-[4-fluoro-2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(100 mg, 0.18 mmol) and morpholine (5.0 mL) yielded, after purificationby flash chromatography (SiO₂: 5 to 20% methanol:methylene chloride), 55mg (48%) of the title compound.

¹NMR, IR

IS-MS, m/e=637 (m+1)

Analysis for C₃₂H₃₇ClN₆O₆:

Calcd: C, 60.33; H, 5.85; N, 13.19;

Found: C, 60.44; H, 6.11; N, 12.96.

B.N-(5-Chloropyridin-2-yl)-3-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)benzoylamino]pyridine-2-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example1-C,3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(300 mg, 0.53 mmol) yielded, after purification by flash chromatography(SiO₂: 5% to 10% methanol in methylene chloride), 320 mg (96%) of thetitle compound.

¹NMR

IS-MS, m/e=537.35 (m+1)

EXAMPLE 5 Preparation of3-[4-(tert-Butyl)-2-(piperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

A. Methyl 4-(tert-Butyl)-2-(1-Boc-piperidin-4-yloxy)-benzoate

To a stirring solution of methyl 4-tert-butyl-2-hydroxybenzoate (9.45 g,45.4 mmol), 1-Boc-piperidin-4-ol (9.6 g, 47.7 mmol) andtriphenylphosphine (12.5 g, 47.7 mmol) in THF (125 mL) was added,dropwise via an addition funnel, a solution of diisopropylazodicarboxylate (9.4 mL, 47.7 mmol) in THF (25 mL). After 72 h, thesolvent was removed in vacuo and the residue was dissolved in a minimalamount of chloroform and vacuum filtered through a pad of silica gel,eluting with a solution of 20% ethyl acetate in hexanes. The filtratewas then concentrated in vacuo and the residue was chromatographed oversilica gel, eluting with a gradient of 5% ethyl acetate in hexanesthrough 20% ethyl acetate in hexanes. The product containing fractionswere combined and concentrated in vacuo to give the ether (12.9 g, 73%)as a thick colorless oil.

¹NMR

ES-MS, m/e 392.3 (m+1)

B. 4-(tert-Butyl)-2-(1-Boc-piperidin-4-yloxy)benzoic acid

To a stirring solution of methyl4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoate (12.9 g, 33 mmol) inp-dioxane (150 mL) was added a solution of LiOH hydrate (2.8 g, 66 mmol)in water (75 mL). The next morning, the solvent was removed in vacuo,and the residue was diluted with water (200 mL) and washed with diethylether. The aqueous phase was then adjusted to pH 3 with citric acid andextracted twice with diethyl ether. The combined ether extracts werethen washed twice with brine, dried with MgSO₄, filtered andconcentrated in vacuo to give 11.3 g (91%) of a white foam.

¹NMR

IS-MS, m/e 378.5 (m+1)

Analysis for C₂₁H₃₁NO₅:

Calcd: C, 66.82; H, 8.28; N, 3.71;

Found: C, 67.06; H, 8.39; N, 3.71.

C.3-[4-(tert-Butyl)-2-(piperidin-4-yloxy)benzoylamino)]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example1-I, 3-amino-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide (626 mg,2.52 mmol) and2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-tert-butylbenzoic acid (500mg, 1.47 mmol) yielded, after deprotection of the coupled product usingmethods substantially equivalent to those described in Example 1-J, 470mg (30%) of the title compound as a trifluoroacetate salt.

¹NMR, IR

IS-MS, m/e=508 (m+1)

Analysis for C₂₇H₃₀ClN₅O₃.H₂O.CF₃CO₂H

Calcd: C, 54.42; H, 5.20;

Found: C, 54.23; H, 4.98.

The 4-tert-butyl-2-hydroxybenzoate for step A above may be prepared asfollows:

D. 3-tert-Butylphenyl methoxymethyl Ether

Chloromethyl methyl ether (MOMCl) (76 mL, 998 mmol) was added in oneportion to a solution of 3-tert-butylphenol (50.04 g, 333 mmol),diisopropylethylamine (Hünig's base) (203 mL, 1.16 mol) and CH₂Cl₂ (225mL) at 0° C. When the addition was complete, the solution was allowed towarm to 23° C., and after 21.5 h additional MOMCl (25 m, 329 mmol) andHünig's base (60 mL, 344 mmol) were added at room temperature. After anadditional 6 h, water (250 mL) was added, and the layers were separated.The organic layer was extracted with water (200 mL), 0.1 N HCl (2×200mL) and saturated NaHCO₃ (200 mL). The organic layer was dried overMgSO₄, filtered and concentrated to yield 66.40 g of amber liquid whichwas purified by flash chromatography (5% EtOAc/hexanes) to provide 50.11g (77%) of pale yellow liquid:

¹H NMR (300 MHz, CDCl₃) δ 7.24 (m, 1H, ArH), 7.07 (m, 2H, ArH), 6.90 (m,1H, ArH), 5.19 (s, 2H, CH₂), 3.50 (s, 3H, CH₃), 1.33 (s, 9H, C(CH₃)₃);

¹³C NMR (DMSO-d₆, 75 MHz) 156.7, 152.3, 128.9, 124.9, 118.6, 113.5,112.7, 93.9, 55.5, 34.3, 30.9 ppm;

IR (CHCl₃) 1488, 1581, 1608, 1602, 2904, 2966 cm⁻¹;

MS (FD+) m/z 194 (100%).

E. 4-tert-Butyl-2-(methoxymethoxy)benzoic Acid

A solution of tert-butyllithium (174 mL, 1.66 M in pentane) was addeddropwise to a solution of 3-tert-butyl-phenyl methoxymethyl ether (49.35g, 254 mmol) and ether (1 liter) at 0° C. over 25 min. The resultingsuspension was maintained at 0° C. for 2 h at which point CO₂ wassparged through for 20 min. The clear solution was allowed to warm, andwater (500 mL) was added. The ether layer was extracted with water (300mL) and was then discarded. Ether (500 mL) was added to the aqueouslayer, and the pH was adjusted from 8-9 to 6 by treatment with 12 N HCl.The aqueous layer was further washed with ether (3×100 mL), and thecombined organic layers were dried (Na₂SO₄), filtered and concen-tratedto 26.18 g (43%) of light yellow solid

(mp 77.7-79.7° C.).

¹H NMR (300 MHz, CDCl₃) δ 8.08 (d, J=8.34 Hz, 1H, 6-ArH), 7.26 (d,J=1.62 Hz, 1H, 3-ArH), 7.20 (dd, J=1.60, 8.27 Hz, 1H, 5-ArH), 5.42 (s,2H, CH₂), 3.57 (s, 3H, CH₃), 1.33 (s, 9H, C(CH₃)₃);

¹³C NMR (DMSO-d₆, 75 MHz) 167.1, 156.2, 155.8, 130.6, 120.0, 118.6,113.9, 95.1, 55.9, 34.8, 30.8 ppm; IR (CHCl₃) 1402, 1423, 1611, 1735,2968, 3019 cm⁻¹;

MS (FD+) m/z 477 (7%), 283 (6%), 238 (100%), 193 (5%).

Anal. for C₁₃H₁₈HO₄:

Calcd: C, 65.53; H, 7.61;

Found: C, 65.82; H, 7.81.

An alternate procedure is as follows: A solution of 3-tert-butylphenylmethoxymethyl ether (42.53 g, 219 mmol), tetramethylethylenediamine(TMEDA, 36.3 mL, 241 mmol) and ether (425 mL) was cooled to −42° C., andn-butyllithium (95.6 mL, 2.52 M in hexanes) was added over 10 min.During the addition the temperature rose to −33° C., and after theaddition it was maintained between −30° C. and −17° C. for 1 h. Thesolution was slowly warmed to −10° C. resulting in a slurry which wasstirred at this temperature for 2 h. Gaseous CO₂ was sparged through theslurry for 20 min. (After an initial exotherm to 16° C. the temperaturefell to −4° C. for the remainder of the addition). The turbid solutionwas allowed to warm to 14° C. overnight under a CO₂ atmosphere, andwater was (200 mL) was added which caused an exotherm, as well aseffervescence. The resulting emulsion was placed in a separatory funnelwith Et₂O (100 mL) and 25% (w/w) NaCl (25 mL). The aqueous layer wasextracted with Et₂O (50 mL) and the combined organic layers werediscarded. The aqueous layer was placed in a beaker with ether (600 mL)and the pH was adjusted from 10-11 to 6 with 12 N HCl. The aqueous layerwas washed with ether (75 mL) and the combined organic layers wereextracted with 0.25 N HCl (75 mL) to remove any residual TMEDA, and with5% (w/w) NaHCO₃ (75 mL). The organic layer was dried (MgSO₄), filteredand evaporated to 28.84 g (55%) of4-tert-butyl-2-(methoxymethoxy)benzoic acid.

F. Methyl 4-tert-Butyl-2-hydroxybenzoate

A solution of 4-tert-butyl-2-(methoxymethoxy)benzoic acid (61.80 g, 259mmol) and MeOH (865 mL) was cooled in an ice bath. Gaseous HCl wassparged through the cold fluid for 30 min to saturate it, and thesolution was then heated to reflux. A Soxhlet extractor containing 3 Åmolecular sieves was used to absorb the water produced in the reaction.After 16 h the heating mantle was removed, and the solution was allowedto cool to ambient temperature. The filtrate was concentrated to a thicksemisolid which was taken up in 1:1 water/CH₂Cl₂ (800 mL). The aqueouslayer was extracted once with CH₂Cl₂ (100 mL), and the combined organiclayers were washed with water (250 mL) and 5% (w/w) NaHCO₃ (200 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated to 49.54 g(92%) of yellow oil:

¹H NMR (300 MHz, CDCl₃) δ 7.74 (d, J=8.42 Hz, 1H, 6-ArH), 7.00 (d,J=1.62 Hz, 1H, 3-ArH), 6.92 (dd, J=1.64, 8.38 Hz, 1H, 5-ArH), 3.93 (s,3H, CO₂Me), 1.30 (s, 9H, C(CH₃)₃);

¹³C NMR (DMSO-d₆, 75 MHz) 169.3, 160.1, 159.4, 129.5, 124.9, 116.8,113.9, 109.9, 52.2, 34.8, 30.5 ppm;

MS (FD+) m/z 326 (100%), 208 (50%).

EXAMPLE 6 Preparation ofN-(5-Chloropyridin-2-yl)-3-[4-isopropyl-2-(piperidin-3-ylmethoxy)benzoylamino]pyridine-2-carboxamideHydrochloride

A. 1-Isopropyl-3-methoxymethoxybenzene

Into methylene chloride (300 mL) was dissolved 3-isopropylphenol (27.24g, 200 mmol). After cooling the solution in an ice bath,diisopropylethyl amine (69.7 mL, 400 mmol) was added in one portion,followed by the dropwise addition of chloromethyl methyl ether (18.9 mL,236 mmol) in methylene chloride (50 mL). The reaction mixture wasgradually allowed to come to room temperature. After 16 h, the reactionmixture was diluted with cold water (500 mL) and methylene chloride. Themixture was shaken in a separatory funnel and the layers were separated.The organic layer was extracted with cold water (2×500 mL), dried(MgSO₄), and concentrated under vacuum. The product was dissolved inether (200 mL) and stirred with 5 N NaOH (200 mL) at room temperaturefor 5 min. The ether layer was separated and extracted with cold 1N HCl(200 mL), dried (MgSO₄), and concentrated under vacuum. The product waschromatographed over silica (0 to 30% EtOAc in hexane gradient), giving20.0 g (56%) of the title compound.

¹NMR

FD-MS, m/e: 180 (m)

B. 4-Isopropyl-2-methoxymethoxybenzoic Acid

Into ether (450 mL) was dissolved 1-isopropyl-3-methoxymethoxybenzene(20.0 g, 111 mmol), and the resulting solution was cooled to −15° C. viaan ice-salt-acetone-bath. Under nitrogen, 1.7 M tert-butyl lithium (78.4mL, 133.2 mmol) was added dropwise over 10 min; and the reaction mixturewas stirred for an additional 10 min. Excess carbon dioxide was bubbledin over 5 min; then the reaction mixture was poured into cold water (400mL) and shaken in a separatory funnel. The aqueous layer was acidifiedwith cold 1 N HCl and shaken with ether (300 mL). The ether layer waswashed with water (300 mL), dried (MgSO₄), and concentrated undervacuum. The product was dissolved in a minimum amount of hexanes, giving19.5 g (78%) of the title compound as a solid on standing at roomtemperature.

¹NMR

IS-MS, m/e: 225 (m+1), 223 (m−1)

C. Methyl 4-Isopropyl-2-hydroxybenzoate

The 4-isopropyl-2-methoxymethoxybenzoic acid (5.3 g, 23.6 mmol) wasdissolved in methylene chloride (75 mL) and MeOH (75 mL). Acetylchloride (1 mL) was added to generate HCl. The reaction mixture wasstirred for 2 h. The reaction was washed with water (2×150 mL), dried(MgSO₄), and concentrated under vacuum. The crude product was dissolvedin methylene chloride (100 mL) and MeOH (30 mL) and to this solution a 2M hexane solution of (trimethylsilyl)diazomethane (11.8 mL, 23.6 mmol)was added dropwise. After 1 h, the solvent was removed under vacuum,giving the title compound as an oil.

¹NMR

D. Methyl2-(1-tert-Butoxycarbonylpiperidin-3-ylmethoxy)-4-isopropylbenzoate

The methyl 4-isopropyl-2-hydroxybenzoate (4.4 g, 22.7 mmol) wasdissolved in THF (100 mL). Then3-(hydroxy-methyl)-1-tert-butoxycarbonylpiperidine (4.88 g, 22.7 mmol)and triphenylphosphine (7.14 g, 27.24 mmol) were added. The mixture wasplaced in an ice bath, and then diisopropyl azodicarboxylate (4.59 g,22.7 mmol) in methylene chloride (15 mL) was added dropwise. Thereaction mixture was allowed to warm gradually to room temperature.After 16 h, the solvent was removed under vacuum. The solid residue wassubjected directly to flash chromatography on silica (0 to 30% EtOAc inhexane gradient), giving the title compound (3.34 g, 43% yield) as anoil.

¹NMR

E. 2-(1-tert-Butoxycarbonylpiperidin-3-ylmethoxy)-4-isopropylbenzoicAcid

The methyl4-isopropyl-2-(1-tert-butoxycarbonyl-piperidin-3-ylmethoxy)benzoate(1.53 g, 3.90 mmol) was dissolved in THF (15 mL). Then LiOH.H₂O (0.36 g,8.58 mmol) in water (5 mL) was added. The mixture was heated at 65° C.for 24 h. The reaction mixture was concentrated in vacuo and thenredissolved in a mixture of EtOAc (100 mL) and cold dilute HCl. Themixture was shaken in a separatory funnel. The layers were separated andthe organic layer was washed with cold water (100 mL), dried (MgSO₄),and concentrated to give 1.23 g of the title compound as an oil.

¹NMR

F.N-(5-Chloropyridin-2-yl)-3-[4-isopropyl-2-(piperidin-3-ylmethoxy)benzoylamino]pyridine-2-carboxamideHydrochloride

Using methods substantially equivalent to those described in Example 1-Iand 1-J,N-(5-chloropyridin-2-yl)-3-[4-isopropyl-2-(piperidin-3-ylmethoxy)benzoylamino]-pyridine-2-carboxamidehydrochloride (50 mg, 0.08 mmol, 7%) was prepared from2-(1-tert-butoxycarbonylpiperidin-3-yl-methoxy)-4-isopropylbenzoic acidand 3-amino-N-(5-chloro-pyridin-2-yl)pyridine-2-carboxamide afterreverse phase HPLC purification.

¹NMR

EXAMPLE 7 Preparation of2-[4-(tert-Butyl)-2-(piperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-3-carboxamideHydrochloride

A. 2-Amino-N-(5-chloropyridin-2-yl)pyridine-3-carboxamide Hydrochloride

To a stirring suspension of 2-aminonicotinic acid (26.9 g, 194 mmol) indichloromethane (120 mL) at 0° C., was added DMF (a few drops), followedby oxalyl chloride (20 mL, 194 mmol). The cold bath was removed, and thesolution was allowed to stir for 60 min at room temperature. Thissolution was then transferred via cannula into a stirring solution of2-amino-5-chloropyridine (25 g, 194 mmol) and pyridine (78 mL, 970 mmol)in dichloromethane (100 mL). After stirring overnight, the precipitatewas filtered and dried to give 32.8 g of solid. The crude product wasrecrystallized from ethanol with activated charcoal to give the amide(12.4 g, 23%) as a white solid.

¹NMR

IS-MS, m/e 249.0 (m+1)

Analysis for C₁₁H₉ClN₄O.HCl:

Calcd: C, 46.33; H, 3.54; N, 19.65; Cl, 24.87;

Found: C, 46.64; H, 3.42; N, 19.63; Cl, 25.23.

B.2-[4-(tert-Butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-3-carboxamideHydrochloride

To a stirring suspension of2-amino-N-(5-chloropyridin-2-yl)pyridine-3-carboxamide hydrochloride(0.80 g, 3.2 mmol) in dichloromethane (20 mL) was added a solution of4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride (5.3 mmol) indichloromethane (20 mL), followed by pyridine (2.1 mL, 26.5 mmol). Theacid chloride formation of4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride wasaccomplished by a procedure equivalent to that described for2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylchloride in Example 1-I but starting from4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoic acid. After stirringovernight, the solvent was removed in vacuo and the residue waschromatographed over silica gel, eluting with a step gradient of 10%ethyl acetate in hexanes through 75% ethyl acetate in hexanes and,finally, with a solution of 15% methanol in dichloromethane. The productcontaining fractions were combined and concentrated in vacuo and theresidue was then dissolved in a solution of 4 N HCl in dioxane. After 10min, the precipitate was collected, washed with ether and dried in vacuoto give 0.347 g of a white solid. The solid was then purified bypreparative RPHPLC. The product containing fractions were combined,partially concentrated in vacuo and lypholized to give the titlecompound (0.079 g, 4.5%) as a fluffy white solid.

¹NMR

IS-MS, m/e 508.3 (m+1)

Analysis for C₂₇H₃₀ClN₅O₃.2.5 HCl.H₂O:

Calcd: C, 52.54; H, 5.63; N, 11.35;

Found: C, 52.38; H, 5.24; N, 11.38.

EXAMPLE 8 Preparation ofN-(5-Chloropyridin-2-yl)-3-[2-[3-(N-formyl-amino)propoxy]-4-(morpholin-4-yl)benzoylamino]pyridine-2-carboxamide

A. Methyl 2-(3-tert-Butoxycarbonylaminopropoxy)-4-fluoro-benzoate

Using a procedure equivalent to Example 1-F, methyl4-fluoro-2-hydroxybenzoate and 3-(tert-butoxycarbonylamino)-propanolgave the ether product as a white solid (20.6 g, 84%).

¹NMR

IS-MS, m/e: 328(m+1).

B. Methyl2-(3-tert-Butoxycarbonylaminopropoxy)-4-(morpholin-4-yl)benzoate

Using methods substantially equivalent to those described in Example1-G, except that the reaction mixture was heated to 130° C., methyl2-(3-tert-butoxycarbonylamino-propoxy)-4-(morpholin-4-yl)benzoate (2.39g, 6.06 mmol, 16%) was prepared from methyl2-(3-tert-butoxycarbonylamino-propoxy)-4-fluorobenzoate and morpholine.

¹NMR (300 MHz, DMSO-d₆): δ 7.60(d, J=9.0 Hz, 1H); 6.84 (m, 1H); 6.50 (d,J=9.0 Hz, 1H); 6.46 (s, 1H); 3.98 (t, J=5.9 Hz, 2H); 3.68 (m, 4H); 3.22(m, 4H); 3.10 (q, J=6.3 Hz, 2H); 1.79 (t, J=6.3 Hz, 2H); 1.33 (s, 9H).

IS-MS, m/e 395.2 (m+1).

Analysis for C₂₀H₃₀N₂O₆:

Calcd: C, 60.90; H, 7.67; N, 7.10;

Found: C, 60.61; H, 7.45; N, 7.08.

C. 2-(3-tert-Butoxycarbonylaminopropoxy)-4-(morpholin-4-yl)benzoic Acid

The methyl2-(3-tert-butoxycarbonylaminopropoxy)-4-(morpholin-4-yl)benzoate (2.34g, 5.93 mmol) was diluted with ethanol (60 mL) and water (60 mL).Potassium hydroxide pellets (1.64 g, 29.2 mmol) were added, and theresulting mixture was heated to 70° C. After 2 h, the reaction mixturewas concentrated in vacuo. The residue was diluted with methylenechloride (200 mL) and extracted with saturated aqueous citric acid (2×50mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated to give the acid (2.24 g, 5.90 mmol, 99%).

¹NMR (300 MHz, DMSO-d₆): δ 7.59(d, J=8.7 Hz, 1H); 6.85 (m, 1H); 6.49 (m,2H); 4.00 (t, J=5.9 Hz, 2H); 3.68 (m, 4H); 3.21 (m, 4H); 3.07 (m, 2H);1.79 (t, J=6.2 Hz, 2H); 1.33 (s, 9H).

IS-MS m/e: 381.4 (m+1).

D.N-(5-Chloropyridin-2-yl)-3-[2-[3-(N-formylamino)-propoxy]-4-(morpholin-4-yl)benzoylaminolpyridine-2-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example1-I, 3-amino-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide (187 mg,0.75 mmol), N,N-dimethyl-formamide (0.2 mL) and2-(3-tert-butoxycarbonylamino-propoxy)-4-(morpholin-4-yl)benzoic acid(300 mg, 0.79 mmol) yielded, after deprotection using methodssubstantially equivalent to those described in Example 1-J, 25 mg (5%)of the title N-formyl compound (which apparently arose from formylationinvolving the DMF under the reaction conditions to afford anN-Boc-N-formyl derivative) as a trifluoroacetate salt.

¹NMR, IR

FD-MS, m/e=538 (m)

Analysis for C₂₆H₂₇ClN₆O₅:

Calcd: C, 57.94; H, 5.05; N, 15.59;

Found: C, 57.73; H, 5.18; N, 15.16.

EXAMPLE 9 Preparation of3-[2-(2-Aminoethoxy)-4-(morpholin-4-yl)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

A. Ethyl 2-(2-tert-Butoxycarbonylaminoethoxy)-4-fluoro-benzoate

To a solution of 2-(tert-butoxycarbonylamino)ethanol (4.34 g, 26.9 mmol)in THF (16 mL) at 0° C. under N₂, was added potassium tert-butoxide(K⁺⁻OtBu, 26.9 mL, 26.9 mmol, 1.0 M in THF). The reaction mixture wasstirred for 20 min at 0° C. during which time a thick slurry formed. Theanion solution was then poured into a solution of ethyl2,4-di-fluorobenzoate (5.00 g, 26.9 mmol) in THF (16 mL) which had beencooled to −65° C. The reaction mixture was allowed to slowly warm toroom temperature and was stirred for 18 h. The mixture was diluted withdichloromethane and washed with water. The water layer was extractedwith additional dichloromethane and the dichloromethane layers combinedand washed with brine, dried, and concentrated in vacuo to give a yellowoil. Purification on silica gel, eluting with a gradient of 4:1 to 3:1hexane:EtOAc, yielded 3.82 g (43.5%) of the ether as a colorless oil.

B. Ethyl2-[2-(2-tert-Butoxycarbonylamino)ethoxy]-4-(morpholin-4-yl)benzoate

Ethyl 2-(2-tert-butoxycarbonylamino)ethoxy-4-fluoro-benzoate (1.75 g,5.35 mmol) and morpholine (1 mL) were heated at 90° C. in a sealed vialfor 7 days. The reaction mixture was diluted with dichloromethane (25mL), washed with water, dried, and the solvent was removed in vacuo.Purification via silica gel chromatography, eluting with a gradient ofhexane and ethyl acetate, yielded 0.791 g (37.5%) of the desired productas a colorless oil.

C. 2-[2-(2-tert-Butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoicAcid

In a manner substantially equivalent to that of Example 1-H, ethyl2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoate (0.790g, 2.00 mmol) yielded 0.617 g (84.1%) of the acid as a white solid.

IS-MS, m/z 367.1 (m+1), 365.2 (m−)

D.3-[2-(2-Aminoethoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example1-I, 3-amino-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide (321 mg,1.29 mmol), N,N-dimethyl-formamide (0.2 mL) and2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoic acid (500mg, 1.36 mmol) yielded, after deprotection of the coupled product usingmethods substantially equivalent to those described in Example 1-J, 20mg (2%) of the title compound as a trifluoroacetate salt.

¹NMR

FD-MS, m/e=497 (m+1)

EXAMPLE 10 Preparation ofN-(5-Chloropyridin-2-yl)-3-[2-[2-(formyl-amino)ethoxy]-4-(morpholin-4-yl)benzoylamino]pyridine-2-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example1-I, 3-amino-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide (321 mg,1.29 mmol), N,N-dimethyl-formamide (0.2 mL) and2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoic acid (500mg, 1.36 mmol) yielded, after deprotection of the coupled product usingmethods substantially equivalent to those described in Example 1-J, 60mg (7%) of the title N-formyl compound (which apparently arose fromformylation involving the DMF under the reaction conditions to afford anN-Boc-N-formyl derivative) as a trifluoroacetate salt.

¹NMR

FD-MS, m/e=525 (m)

EXAMPLE 11 Preparation ofN-(5-Chloropyridin-2-yl)-3-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)benzoylamino]pyridine-2-carboxamideTrifluoroacetate. (Resynthesis of Example 4)

Using methods substantially equivalent to those described in Example1-G,3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-fluorobenzoylamino)]-N-(5-chloro-pyridin-2-yl)pyridine-2-carboxamide(300 mg, 0.53 mmol) and morpholine (5 mL) yielded, after deprotection ofthe coupled product using methods substantially equivalent to thosedescribed in Example 1-J, 400 mg (68%) of the title compound as atrifluoroacetate salt.

¹NMR, IR

IS-MS, m/e=537 (m)

Analysis for C₂₇H₃₀ClN₆O₄.5 CF₃CO₂H:

Calcd: C, 40.14; H, 3.10;

Found: C, 40.41; H, 3.50.

EXAMPLE 12 Preparation ofN-(5-Chloropyridin-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-3-yl)benzoylamino]pyridine-4-carboxamideTrifluoroacetate

A. 3-Aminopyridine-4-carboxylic Acid

A solution of 10% aqueous NaOH (416 mL) was cooled to 0° C. and treatedwith bromine (28.2 g 176 mmol) portionwise via pipette while keeping thetemperature below 5° C. To this mixture was added3,4-pyridinedicarboximide (25.78 g, 174 mmol), and the cooling bath wasremoved. The reaction was heated to 80° C. for 45 min, then allowed tocool in an ice bath. When the temperature fell to 60° C., the dropwiseaddition of HOAc (50 mL) was started. Cooling was continued until thetemperature reached 15° C. A yellow precipitate formed. The solid wasfiltered, rinsed with water, then dried under vacuum to give 14.9 g ofproduct (108 mmol, 62%).

¹NMR

IS-MS, m/e 139 (m+1)

B. Methyl 3-Aminopyridine-4-carboxylate

Using methods substantially equivalent to those described in the secondpart of Example 1-E, methyl 3-amino-pyridine-4-carboxylate was preparedin a 75% yield from 3-aminopyridine-4-carboxylic acid.

¹NMR

FD-MS, m/e 153 (m+1)

C. Methyl3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxylate

A solution of2-(1-tert-butoxycarbonylpiperidin-4-yl-oxy)-4-(pyrrolidin-1-yl)benzoicacid (2 g, 5.1 mmol) in CH₂Cl₂ (15 mL) was cooled to 0° C. and treatedwith a 2 M CH₂Cl₂ solution of oxalyl chloride (5.1 mL). The reactionmixture was stirred at 0° C. for 1 h, concentrated to dryness, thenredissolved in CH₂Cl₂ (5 mL). This solution was added dropwise to a coldsolution of methyl 3-amino-pyridine-4-carboxylate, pyridine (2 mL), andCH₂Cl₂ (5 mL). The reaction mixture was slowly warmed to roomtemperature and stirred overnight. The mixture was concentrated todryness, diluted with saturated aqueous NaHCO₃ (50 mL), and extractedwith 10% MeOH in EtOAC (3×). The extracts were dried over MgSO₄ andconcentrated to a dark oil which was purified by flash chromatography,eluting with Hex/THF/Et₃N 65/30/5, to give 1.92 g (71%) of the amide.

¹NMR

FD-MS, m/e 525 (m+1)

D.3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxylicAcid

A solution of methyl3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxylate(2.78 g, 5.3 mmol) in MeOH (100 mL) and THF (50 mL) was treated with 1 NNaOH (11 mL) and stirred at ambient temperature for 4 h. The reactionwas quenched with glacial acetic acid (1 g) and concentrated to dryness.The residue was mixed with brine (50 mL) and extracted with 10% MeOH inCHCl₃ (3×). The extracts were dried over MgSO₄ and concentrated to 2.2 g(4.3 mmol, 81%) of a yellow solid.

¹NMR

FD-MS, m/e 510 (m+)

E.2-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-one

A mixture of3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxylic acid (2.2 g, 4.1 mmol) and CH₂Cl₂(500 mL) was cooled to 0° C. and treated with a 2 M CH₂Cl₂ solution ofoxalyl chloride (5 mL). The reaction mixture was stirred at 0° C. for 1h, then washed with saturated aqueous NaHCO₃ (50 mL). The layers wereseparated and the organic layer was dried over MgSO₄ then concentratedto give 1.8 g (3.7 mmol, 89%) of a yellow solid.

¹NMR

IS-MS 523 (m+CH₃OH)

Analysis for C₂₇H₃₂N₄O₅:

Calcd: C, 65.84; H, 6.55; N, 11.37;

Found: C, 65.75; H, 6.56; N, 11.13.

F.3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-4-carboxamide

A solution of 2-amino-5-chloropyridine (52 mg, 0.4 mmol) in THF (10 mL)was cooled to 0° C. and treated with a 1 M diethyl ether solution ofallylmagnesium bromide (0.4 mL). The mixture was stirred for 5 minutesbefore adding2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-one(100 mg, 0.2 mmol). The reaction mixture was stirred overnight atambient temperature then concentrated to dryness under vacuum. Theresidue was treated with brine (5 mL) and CHCl₃ (20 mL). The layers wereseparated and the organic layer was chromatographed using 1% MeOH inCHCl₃ to give 125 mg (0.2 mmol, 99%) of product as a solid.

¹NMR

FD-MS, m/e 621 (m+1)

G.N-(5-Chloropyridin-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxamideTrifluoroacetate

The3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-4-carboxamide(109 mg, 0.18 mmol) was dissolved in CH₂Cl₂ (2 mL) with anisole (1 mL).The solution was treated with trifluoroacetic acid (1 mL) at roomtemperature for 2 h. The mixture was concentrated to dryness undervacuum, rinsed with hexanes, and sonicated with diethyl ether (5 mL) for5 min to give 120 mg (0.16 mmol, 89%) of the title product.

¹NMR

FD-MS, m/e 521 (m+1)

Analysis for C₂₇H₂₉ClN₆O₃.1.6 CF₃COOH.H₂O:

Calcd: C, 50.28; H, 4.55; N, 11.65;

Found: C, 50.54; H, 4.31; N, 11.80.

EXAMPLE 13 Preparation ofN-(4-Methylthiazol-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxamideTrifluoroacetate

A.3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(4-methylthiazol-2-yl)-pyridine-4-carboxamide

Using methods substantially equivalent to those described in Example12-F,3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(4-methylthiazol-2-yl)pyridine-4-carboxamidewas prepared in an 87% yield from2-[2-(1-tert-butoxycarbonylpiperidin-4-yl-oxy)-4-(pyrrolidin-1-yl)phenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-oneand 2-amino-4-methylthiazole.

¹NMR

FD-MS, m/e 607 (m+1)

B.N-(4-Methylthiazol-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example12-G,N-(4-methylthiazol-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-pyridine-4-carboxamidetrifluoroacetate was prepared in a 74% yield from3-[4-(pyrrolidin-1-yl)-2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)benzoylamino]-N-(4-methylthiazol-2-yl)pyridine-4-carboxamide.

¹NMR

FD-MS, m/e 507 (m+1)

Analysis for C₂₆H₃₀N₆SO₃.2 CF₃COOH.H₂O:

Calcd: C, 47.87; H, 4.55; N, 11.17;

Found: C, 47.77; H, 4.22; N, 11.03.

EXAMPLE 14 Preparation of3-[2-(Piperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]-N-(thiazol-2-yl)pyridine-4-carboxamideTrifluoroacetate

A.3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(thiazol-2-yl)pyridine-4-carboxamide

Using methods substantially equivalent to those described in Example12-F,3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(thiazol-2-yl)pyridine-4-carboxamidewas prepared in an 87% yield from2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-oneand 2-aminothiazole.

¹NMR

IS-MS, m/e 593 (m+1)

B.3-[2-(Piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoyl-amino]-N-(thiazol-2-yl)pyridine-4-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example12-G,3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(thiazol-2-yl)pyridine-4-carboxamidetrifluoroacetate was prepared in a 75% yield from3-[4-(pyrrolidin-1-yl)-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)benzoylamino]-N-(thiazol-2-yl)pyridine-4-carboxamide.

¹NMR

FD-MS, m/e 493 (m+1)

Analysis for C₂₅H₂₈N₆SO₃.2 CF₃COOH:

Calcd: C, 48.33; H, 4.20; N, 11.66;

Found: C, 48.09; H, 4.17; N, 11.60.

EXAMPLE 15 Preparation ofN-(5-Bromothiazol-2-yl)-3-[2-(piperidin-4-yl-oxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxamideTrifluoroacetate

A.N-(5-Bromothiazol-2-yl)-3-(2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxamide

Using methods substantially equivalent to those described in Example12-F,N-(5-bromothiazol-2-yl)-3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]pyridine-4-carboxamidewas prepared in a 47% yield from2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-oneand 2-amino-5-bromothiazole.

¹NMR

FD-MS, m/e 671 (m+1)

B.N-(5-Bromothiazol-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example12-G,N-(5-bromothiazol-2-yl)-3-(2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-pyridine-4-carboxamidetrifluoroacetate was prepared in a 75% yield fromN-(5-bromothiazol-2-yl)-3-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoyl-amino]pyridine-4-carboxamide.

¹NMR

FD-MS, m/e 571,573 (m+1)

Analysis for C₂₅H₂₇BrN₆SO₃.1.5 CF₃COOH.0.5H₂O:

Calcd: C, 44.75; H, 3.96; N, 11.18;

Found: C, 45.05; H, 4.03; N, 11.39.

EXAMPLE 16 Preparation of3-[4-(tert-Butyl)-2-(piperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-4-carboxamide

A. Methyl3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoylamino]pyridine-4-carboxylate

Using methods substantially equivalent to those described in Example12-C, methyl3-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoylamino]-pyridine-4-carboxylatewas prepared in a 32% yield from methyl 3-aminopyridine-4-carboxylateand 2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoicacid.

¹NMR

FD-MS, m/e 512 (m+1)

B.2-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-tert-butylphenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-one

A solution of methyl3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(tert-butyl)benzoylamino]pyridine-4-carboxylate(1.2 g, 2.3 mmol) in THF (100 mL) was treated with a 1 M aqueoussolution of LiOH followed by MeOH (30 mL). The reaction mixture wasstirred at ambient temperature for 2 h, then neutralized with formicacid (200 μL). The resulting solution was, concentrated to dryness undervacuum, mixed with toluene and reconcentrated to dryness.

The residue was mixed with CH₂Cl₂ (800 mL), cooled to 0° C., and treatedwith a 2 M CH₂Cl₂ solution of oxalyl chloride (6 mL) and 2 drops of DMF.The reaction mixture was stirred overnight at ambient temperature. Themixture was concentrated under vacuum to dryness and chromatographed onsilica using 30% EtOAc in hexanes to give 620 mg (56%) of the titlecompound as an oil.

¹NMR

C.3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-4-carboxamide

A mixture of2-[2-(1-tert-butoxycarbonylpiperidin-4-yl-oxy)-4-tert-butylphenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-one(100 mg, 0.21 mmol), KCN (100 mg), 5-chloro-2-aminopyridine (53 mg, 0.42mmol), and dry DMF (2 mL) was heated at 70° C. for 4 h, then quenchedwith brine (25 mL). The mixture was extracted with 10% MQOH in EtOAc(2×20 mL), and the combined extracts were washed with brine (3×100 mL)then dried over MgSO₄. After filtering, the filtrate was concentrated toan oil which was purified by chromatography using 60% EtOAc in hexanesto give 30 mg of an oil which crystallized.

¹NMR

FD-MS, m/e 608 (m+1)

D.3-[4-(tert-Butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-4-carboxamide

The3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-4-carboxamide(60 mg, 0.1 mmol) was mixed with anisole (1 mL) and CH₂Cl₂ (2 mL) thentreated with trifluoroacetic acid (1 mL). The reaction was stirred atambient temperature for 4 h, concentrated under vacuum to dryness andmixed with CH₂Cl₂. This was filtered through a 1 g SCX ion exchangecolumn using 2 M NH₃ in MeOH. Concentration to dryness gave 32 mg of thetitle compound as a solid.

¹NMR

FD-MS, m/e 508 (m+)

EXAMPLE 17 Preparation of3-[2-(Piperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]-N-(pyridin-2-yl)thiophene-2-carboxamide Trifluoroacetate

A. Methyl3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-2-carboxylate

Using methods substantially equivalent to those described in Example12-C, methyl3-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-thiophene-2-carboxylatewas prepared in a 58% yield from2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoicacid and methyl 3-aminothiophene-2-carboxylate.

¹NMR

FD-MS, m/e 530 (m+1)

B.3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-2-carboxylicAcid

A solution of the methyl3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-thiophene-2-carboxylate(3.8 g, 7.2 mmol) and EtOH (100 mL) was treated with a solution of KOH(0.88 g) in water (80 mL). The reaction mixture was refluxed overnight,quenched with glacial acetic acid (1.5 mL) and concentrated undervacuum. The resulting aqueous mixture was extracted with EtOAc (2×100mL). The combined extracts were dried over MgSO₄ and concentrated togive 3.5 g (6.8 mmol, 94%) of the acid as a foam.

¹NMR

FD-MS, m/e 516 (m+1)

C.2-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(1-pyrroldinyl)phenyl]-4H-thieno[3,2-d][1,3]oxazin-4-one

A solution of3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-2-carboxylicacid (3.4 g, 6.6 mmol) in dry DMF (35 mL) was treated with1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (25 g, 13.2mmol). The reaction was stirred at ambient temperature for 1 h. Themixture was poured into brine (300 mL) and extracted with EtOAc (3×100mL). The combined extracts were washed with water (300 mL) then withbrine (3×300 mL). The organic layer was dried over MgSO₄ andconcentrated to a solid which was purified by chromatography on silicausing 30% EtOAc in hexanes to give 3.4 g of a yellow solid.

¹NMR

FD-MS, m/e 498 (m+1)

D.3-[2-(Piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoyl-amino]-N-(pyridin-2-yl)thiophene-2-carboxamideTrifluoroacetate

A solution of 2-aminopyridine (56.7 mg, 0.6 mmol) in dry THF (5 mL) wastreated with a 1 M diethyl ether solution of allylmagnesium bromide (0.6mL). After 5 min, a solution of2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(1-pyrroldinyl)phenyl]-4H-thieno[3,2-d][1,3]oxazin-4-one(100 mg, 0.2 mmol) in dry THF (5 mL) was added. The reaction was stirredovernight, concentrated to dryness, and partitioned between saturatedaqueous NaHCO₃ (2 mL) and CH₂Cl₂ (5 mL). The organic layer was purifiedby 2 chromatographic procedures using 55/40/5 hexanes/THF/Et₃N.

The recovered solid was dissolved in CH₂Cl₂ (10 mL) with anisole (1 mL)and treated with trifluoroacetic acid (2 mL) overnight at ambienttemperature. The reaction mixture was concentrated under vacuum, mixedwith diethyl ether (10 mL), and sonicated for 15 min to give 87 mg ofthe title compound as a solid (61%).

FD-MS, m/e 492 (m+1)

EXAMPLE 18 Preparation ofN-(5-Chloropyridin-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-2-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example17-D,N-(5-chloropyridin-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-thiophene-2-carboxamidetrifluoroacetate was prepared in a 42% yield from2-[2-(1-tert-butoxycarbonylpiperidin-4-yl-oxy)-4-(1-pyrroldinyl)phenyl]-4H-thieno[3,2-d][1,3]oxazin-4-one(100 mg, 0.2 mmol) and 2-amino-5-chloropyridine.

FD-MS, m/e 526 (m+1)

Analysis for C₂₅H₂₈ClN₅SO₃.CF₃COOH.0.5H₂O:

Calcd: C, 51.81; H, 4.66; N, 10.79;

Found: C, 52.15; H, 4.44; N, 10.56.

EXAMPLE 19 Preparation ofN-(5-Chloropyridin-2-yl)-4-[4-(dimethyl-amino)-2-(piperidin-4-yloxy)benzoylamino]thiophene-3-carboxamideTrifluoroacetate

A. Methyl2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoate

The 4-dimethylamino compound was obtained in the following preparationin which the dimethylamino group was derived from in situ decompositionof the solvent DMF: A mixture of methyl2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate (6.45 g,18.25 mmol), morpholine (8 g, 91.26 mmol), Cs₂CO₃ (11.8 g, 36.5 mmol),and DMF (10 mL) was heated 3 days at 110° C. The reaction mixture waspoured into brine (100 mL) and extracted with EtOAc (3×100 mL). Thecombined extracts were washed with brine (3×200 mL), dried over MgSO₄,and concentrated to an oil which was purified by chromatography onsilica using 25% EtOAc in hexanes to give 4.1 g (59%) of product as awhite solid.

¹NMR

FD-MS, m/e 379 (m+1)

B. 2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoicacid

Using methods substantially equivalent to those described in Example12-D,2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(dimethylamino)benzoicacid was prepared in a 88% yield from methyl2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoate.

¹NMR

FD-MS, m/e 364 (m+)

Analysis for C₁₉H₂₈N₂O₅:

Calcd: C, 62.62; H, 7.74; N, 7.69;

Found: C, 62.70; H, 7.79; N, 7.63.

C. Methyl4-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoylamino]thiophene-3-carboxylate

Using methods substantially equivalent to those described in Example12-C, methyl4-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoylamino]-thiophene-3-carboxylatewas prepared in a 51% yield from2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(dimethyl-amino)benzoicacid and methyl 4-aminothiophene-3-carboxylate.

¹NMR

IS-MS 504 (m+1)

Analysis for C₂₅H₃₃N₃SO₆:

Calcd: C, 59.62; H, 6.60; N, 8.34;

Found: C, 59.67; H, 6.65; N, 8.37.

D.2-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(dimethylamino)phenyl]-4H-thieno[3,4-d][1,3]oxazin-4-one

A solution of methyl4-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(dimethylamino)benzoylamino]thiophene-3-carboxylate(2.3 g, 4.6 mmol) in MeOH (100 mL) and THF (50 mL) was treated with asolution of 1 N aqueous NaOH (10 mL) at 60° C. for 24 h. The mixture wasconcentrated to dryness, mixed with brine (25 mL) and glacial aceticacid (0.65 mL), then extracted with CHCl₃ (2×100 mL). The extracts weredried over MgSO₄, cooled to 0° C. and treated with Et₃N (1 g) followedby a 2 M CH₂Cl₂ solution of oxalyl chloride (3.5 mL). The mixture wasstirred overnight, concentrated to dryness, and treated sequentiallywith potassium carbonate (11 g), THF (20 mL), water (20 mL), anddi-tert-butyl dicarbonate (8 g). The mixture was stirred overnight,diluted with more THF (50 mL) and treated with NaCl (20 g). The organiclayer was separated, dried over MgSO₄, and concentrated to an oil whichwas purified by silica chromatography using 15% EtOAc in hexanes to give2 g of product as an oil.

IS-MS, m/e 472 (m+1)

E.N-(5-Chloropyridin-2-yl)-4-[4-(dimethylamino)-2-(piperidin-4-yloxy)benzoylamino]thiophene-3-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example17-D and 12-G,N-(5-chloropyridin-2-yl)-4-[4-(dimethylamino)-2-(piperidin-4-yloxy)benzoylamino]-thiophene-3-carboxamidetrifluoroacetate was prepared in a 20% yield from2-[2-(1-tert-butoxycarbonylpiperidin-4-yl-oxy)-4-(dimethylamino)phenyl]-4H-thieno[3,4-d][1,3]oxazin-4-oneand 2-amino-5-chloropyridine.

¹NMR

IS-MS 500 (m+1)

Analysis for C₂₄H₂₆ClN₅SO₃.CF₃COOH.0.1H₂O:

Calcd: C, 50.71; H, 4.45; N, 11.37;

Found: C, 50.62; H, 4.41; N, 11.05,

EXAMPLE 20 Preparation ofN-(4-Chlorophenyl)-4-[4-(dimethylamino)-2-(piperidin-4-yloxy)benzoylamino]thiophene-3-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example17-D,N-(4-chlorophenyl)-4-[4-(dimethylamino)-2-(piperidin-4-yloxy)benzoylamino]-thiophene-3-carboxamidetrifluoroacetate was prepared in a 14% yield from2-[2-(1-tert-butoxycarbonylpiperidin-4-yl-oxy)-4-(dimethylamino)phenyl]-4H-thieno[3,4-d][1,3]oxazin-4-oneand 4-chloroaniline.

¹NMR

IS-MS, m/e 499 (m+1)

Analysis for C₂₅H₂₇ClN₄SO₃.CF₃COOH.0.1H₂O:

Calcd: C, 52.74; H, 4.62; N, 9.11;

Found: C, 52.40; H, 4.55; N, 8.74.

EXAMPLE 21 Preparation ofN-(5-Chloropyridin-2-yl)-4-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-3-carboxamideTrifluoroacetate

A. Methyl4-[2-(Piperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]thiophene-3-carboxylate

Using methods substantially equivalent to those described in Example12-C, methyl4-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-3-carboxylatewas prepared in a 67% yield from2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoicacid and methyl 4-aminothiophene-3-carboxylate.

¹NMR

FD-MS, m/e 530 (m+1)

Analysis for C₂₇H₃₅N₃O₆S:

Calcd: C, 61.23; H, 6.66; N, 7.93;

Found: C, 61.13; H, 6.60; N, 7.89.

B.4-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-3-carboxylicAcid

A solution of methyl4-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-3-carboxylate(4.4 g, 8.3 mmol) in EtOH (100 mL) was treated with water (100 mL) andKOH (1.92 g, 34.2 mmol). The reaction mixture was refluxed for 20 h. Itwas then quenched with glacial acetic acid (3 g), concentrated undervacuum, and extracted with EtOAc (3×100 mL). The extracts were driedover MgSO₄ and concentrated to give 4.1 g (7.9 mmol, 96%) of a foam.

¹NMR

FD-MS, m/e 516 (m+1)

C.2-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(1-pyrroldinyl)phenyl]-4H-thieno[3,4-d][1,3]oxazin-4-one

Using methods substantially equivalent to those described in Example17-C,2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(1-pyrroldinyl)phenyl]-4H-thieno[3,4-d][1,3]oxazin-4-onewas prepared in a 56% yield from4-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-3-carboxylicacid.

¹NMR

IS-MS 498 (m+1)

Analysis for C₂₆H₃₁N₃SO₅:

Calcd: C, 61.64; H, 6.37; N, 8.29;

Found: C, 61.72; H, 6.23; N, 8.33.

D.4-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-thiophene-3-carboxamide

Using methods substantially equivalent to those described in Example12-F,4-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)thiophene-3-carboxamidewas prepared in a 66% yield from2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(1-pyrroldinyl)phenyl]-4H-thieno[3,4-d][1,3]oxazin-4-one.

¹NMR

IS-MS 626 (m+1)

Analysis for C₃₁H₃₆ClN₅SO₅:

Calcd: C, 59.46; H, 5.79; N, 11.18;

Found: C, 59.20; H, 5.76; N, 10.92.

E.N-(5-Chloropyridin-2-yl)-4-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]thiophene-3-carboxamideTrifluoroacetate

Using methods substantially equivalent to those described in Example12-G,N-(5-chloropyridin-2-yl)-4-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-thiophene-3-carboxamidetrifluoroacetate was prepared in a 66% yield from4-[2-(1-tert-butoxycarbonylpiperidin-4-yl-oxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)thiophene-3-carboxamide.

¹NMR

IS-MS 526 (m+1)

Analysis for C₂₆H₂₈ClN₅SO₃.CF₃CO₂H.H₂O

Calcd: C, 51.10; H, 4.75; N, 10.64;

Found: C, 51.34; H, 4.38; N, 10.49.

EXAMPLE 22 Preparation of2-[4-tert-Butyl-2-(piperidin-4-yloxy)-benzylamino]-N-(4-chlorophenyl)pyridine-3-carboxamide

A. 4-tert-Butyl-2-(1-Boc-piperidin-4-yloxy)benzyl Alcohol

The alcohol may be prepared as follows: To a solution ofborane-trimethylamine complex (1.35 mL of a 1 M solution intetrahydrofuran) in tetrahydrofuran (3 mL) stirring at 0° C., a solutionof 4-tert-butyl-2-(1-Boc-piperidine-4-yl-oxy)benzoic acid (0.51 g, 1.35mmol) in tetrahydrofuran (7 mL) was added slowly via cannula. After theaddition was complete the reaction mixture was stirred at roomtemperature for 4 h, then an additional amount of borane-trimethylaminecomplex was added (1.35 mL of a 1 M solution in tetrahydrofuran). Thereaction mixture was stirred at room temperature for another 2 h. Afterquenching with ice, the mixture was partitioned between brine anddichloromethane. The organic layer was separated and the aqueous layerwas extracted with dichloromethane (3×). The combined organic layerswere dried with magnesium sulfate, filtered, and concentrated in vacuoto a residue (0.42 g, 86%) which was identified as the title compoundand used directly in the next step without further purification.

¹NMR

FD-MS, m/e 364.1 (m+1).

B. N-[4-tert-Butyl-2-(1-Boc-piperidin-4-yloxy)benzyl]-phthalimide

To a solution of 4-tert-butyl-2-(1-Boc-piperidin-4-yl-oxy)benzyl alcohol(0.310 g, 0.85 mmol), phthalimide (0.125 g, 0.85 mmol), andtriphenylphosphine (0.224 g, 0.85 mmol) in 5 mL dry tetrahydrofuran at−10° C. was added a 0.5 M solution of diethyl azodicarboxylate intetrahydro-furan (0.135 mL, 0.85 mmol). The reaction mixture was allowedto slowly warm to room temperature for 16 h. The solvent was removed invacuo; and the crude material purified by chromatography over silica,using an eluent of 10-20% ethyl acetate in hexanes, to afford thesubstituted phthalimide (0.258 g, 61%).

¹NMR

FD-MS, m/e 493 (m+1)

C. 4-tert-Butyl-2-(1-Boc-piperidin-4-yloxy)benzylamine

To a solution ofN-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzyl]phthalimide (0.243 g,0.49 mmol) in 3 mL absolute ethanol was added hydrazine (0.062 mL, 1.98mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 2 h, diluted with methylene chloride; and the resultingwhite solid filtered off. The solvent of the filtrate was evaporated invacuo. The remaining material was re-dissolved in a minimum amount ofchloroform, sonicated, and any additional white solid filtered off. Thefiltrate was concentrated in vacuo to afford the amine (0.170 g, 95%).

D. N-(4-Chlorophenyl)-2-chloronicotinamide

To a solution of nicotinoyl chloride (0.500 g, 2.84 mmol) in 15 mL of1,2-dichloroethane was added 4-chloroaniline (0.432 g, 3.41 mmol) andtriethylamine (0.400 mL, 2.84 mmol), respectively. The reaction mixturewas stirred at room temperature for 1 h before it was washed with water(2×), brine (1×), dried over Na₂SO₄, and the solvent removed in vacuo.The crude material was purified by chromatography over silica, using aneluent of 2% (2 M NH₃ in methanol) in chloroform, to afford the amide(0.758 g, 100%).

¹NMR

E.2-[4-tert-Butyl-2-(1-Boc-piperidin-4-yloxy)benzyl-amino)]N-(4-chlorophenyl)pyridine-3-carboxamide

N-(4-Chlorophenyl)-2-chloronicotinamide (0.190 g, 0.70 mmol),4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzyl-amine (0.170 g, 0.47mmol), and triethylamine (0.065 mL, 0.47 mmol) were placed in a pressuretube and diluted with 1 mL of absolute ethanol. The reaction vessel washeated at 100° C. for 3 days. The solvent was removed, and the remainingtriethylamine was removed by azeotroping with toluene. The crudematerial was purified by chromatography over silica, using an eluentgradient of 20-40% ethyl acetate in hexanes to afford the named product(0.190 g, 68%).

¹NMR

FD-MS m/e 593 (m+1)

F.2-[4-tert-Butyl-2-(piperidin-4-yloxy)benzylamino)]-N-(4-chlorophenyl)pyridine-3-carboxamide

To a solution of2-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzylamino)]-N-(4-chlorophenyl)pyridine-3-carboxamide(0.110 g, 0.19 mmol) in 2 mL of methylene chloride was addedtrifluoroacetic acid (0.14 mL, 1.86 mmol). The reaction mixture wasstirred at room temperature for 3 h. The solvent was removed in vacuo,and the remaining oil was partitioned between ethyl acetate andsaturated NaHCO₃. The aqueous layer was extracted with ethyl acetate(2×). The ethyl acetate extracts were combined and washed with brine(1×), dried over Na₂SO₄, and the solvent removed in vacuo. The crudematerial was purified by chromatography over silica, using an eluent of5-6% (2 M NH₃ in methanol) in chloroform, to afford the title compound(0.920 g, 100%).

¹NMR

FD-MS m/e 493 (m+1)

EXAMPLE 23 Preparation of2-[2-(2-Aminoethoxy)-4-isopropylbenzylamino]-N-(4-chlorophenyl)pyridine-3-carboxamide

A. 4-Isopropyl-2-(methoxymethoxy)benzyl Alcohol

To a solution of 4-isopropyl-2-(methoxymethoxy)benzoic acid, which maybe prepared as described in Exmple 6-B, (2.40 g, 11.0 mmol) and4-methylmorpholine (1.18 mL, 11.0 mmol) in 50 mL dry tetrahydrofuran at−10° C. was added dropwise ethyl chloroformate (1.02 mL, 11.0 mmol).After stirring at −10° C. for 20 min, sodium borohydride (1.21 g, 33.0mmol) was added all at once. Methanol (150 mL) was cautiously addeddropwise. Once the vigorous evolution of carbon dioxide hadsignificantly decreased, the remaining methanol was added. Stirring wascontinued for 30 min, and the reaction was quenched with 10% acetic acidin water. The volatile solvents were removed, and the remaining materialwas diluted with ether. The ether was extracted with saturated NaHCO₃(2×), water (2×), brine (1×), and dried over MgSO₄. The crude materialwas purified by chromatography over silica, using an eluent gradient of10-30% ethyl acetate in hexanes, to afford the alcohol (1.16 g, 50%).

¹NMR

FD-MS m/e 193 ([m-H₂O]+1)

Analysis for C₁₂H₁₈O₃:

Calcd: C, 68.55; H, 8.63;

Found: C, 68.20; H, 9.01.

B. N-[4-Isopropyl-2-(methoxymethoxy)benzyl]phthlalimide

Using a procedure similar to that described in Example 22-B, thesubstituted phthalimide was obtained (1.50 g, 81%) from4-isopropyl-2-(methoxymethoxy)benzyl alcohol.

¹NMR

FD-MS m/e 340 (m+1)

Analysis for C₂₀H₂₁NO₄:

Calcd: C, 70.78; H, 6.24; N, 4.13;

Found: C, 70.92; H, 6.10; N, 4.21.

C. 4-Isopropyl-2-(methoxymethoxy)benzylamine hydrochloride

Using a procedure substantially similar to that described in Example22-C, 4-isopropyl-2-(methoxymethoxy)-benzylamine was prepared. Thehydrochloride salt was prepared by dissolving the free base in ethylacetate and treating with an excess of 1 N HCl in ether. The solvent wasremoved to afford the salt (0.750 g, 81%).

¹NMR

FD-MS m/e 210 (m+1)

D.N-(4-Chlorophenyl)-2-[4-isopropyl-2-(methoxymethoxy)-benzylamino]pyridine-3-carboxamide

Using a procedure substantially similar to that described in Example22-E,N-(4-chlorophenyl)-2-[4-isopropyl-2-(methoxymethoxy)benzylamino]pyridine-3-carboxamidewas prepared (0.820 g, 52%) from4-isopropyl-2-(methoxymethoxy)benzylamine andN-(4-chlorophenyl)-2-chloronicotinamide.

¹NMR

FD-MS m/e 440 (m+1)

Analysis for C₂₄H₂₆ClN₃O₃:

Calcd: C, 65.52; H, 5.96; N, 9.55;

Found: C, 65.69; H, 6.17; N, 9.35.

E.N-(4-Chlorophenyl)-2-[2-hydroxy-4-isopropylbenzyl-amino]pyridine-3-carboxamide

To a solution ofN-(4-chlorophenyl)-2-[4-isopropyl-2-(methoxymethoxy)benzylamino]pyridine-3-carboxamide(0.670 g, 1.52 mmol) in trifluoroacetic acid was added 4 mL of water.The reaction mixture was stirred at room temperature for 5 h. Thevolatile solvent was removed in vacuo, and the remaining aqueoussolution was neutralized with 1 N NaOH. The aqueous layer was extractedwith ethyl acetate (2×). The ethyl acetate was then washed with brine(1×), dried over Na₂SO₄ and the solvent removed in vacuo. The crudematerial was purified by chromatography over silica, using an eluentgradient of 10-30% tetrahydrofuran in hexanes, to afford the productalcohol (0.420 g, 70%).

¹NMR

FD-MS m/e 396 (m+1)

F. 2-[2-(N-Boc-Aminoethoxy)-4-isopropylbenzylamino]-N-(4-chlorophenyl)pyridine-3-carboxamide

To a solution ofN-(4-chlorophenyl)-2-[2-hydroxy-4-isopropylbenzylamino]pyridine-3-carboxamide(0.050 g, 0.13 mmol), triphenylphosphine (0.033 g, 0.13 mmol) andN-Boc-ethanolamine (0.018 mg, 0.11 mmol) in 0.3 mL tetrahydrofuran at−10° C. was added a solution of diethyl azodicarboxylate (0.02 mL, 0.13mmol) in 0.3 mL tetrahydrofuran. The reaction was stirred at roomtemperature for 3 days. The solvent was removed in vacuo; and the crudematerial was purified by chromatography over silica, using an eluentgradient of 20-30% ethyl acetate in hexanes, to afford the named product(0.02 g, 30%).

¹NMR

FD-MS m/e 539 (m+1)

G.2-[2-(2-Aminoethoxy)-4-isopropylbenzylamino]-N-(4-chlorophenyl)pyridine-3-carboxamide

2-[2-(N-Boc-Aminoethoxy)-4-isopropylbenzylamino]-N-(4-chlorophenyl)pyridine-3-carboxamide(0.02 g, 0.04 mmol) was dissolved in 2 mL of a 1:3 mixture oftrifluoroacetic aicd:methylene chloride. The reaction mixture wasstirred at room temperature for 30 min. The solvent was removed, and thematerial was purified by ion exchange chromatography to afford the titlecompound (0.014 g, 88%) as the free base.

¹NMR

FD-MS m/e 439 (m+1)

EXAMPLE 24 Preparation of2-[2-(3-Aminopropoxy)-4-isopropylbenzyl-amino)]-N-(4-chlorophenyl)pyridine-3-carboxamide

A.2-[2-(N-Boc-3-Aminopropoxy)-4-isopropylbenzylamino)]-N-(4-chlorophenyl)pyridine-3-carboxamide

Using a procedure substantially similar to that described in Example23-F,2-[2-(N-Boc-3-aminopropoxy)-4-isopropylbenzylamino)]-N-(4-chlorophenyl)pyridine-3-carboxamidewas prepared (0.02 g, 25%) from2-[2-hydroxy-4-isopropylbenzylamino]-N-(4-chlorophenyl)pyridine-3-carboxamideand N-Boc-3-aminopropanol.

¹NMR

FD-MS m/e 553 (m+1)

B.2-[2-(3-Aminopropoxy)-4-isopropylbenzylamino)]-N-(4-chlorophenyl)pyridine-3-carboxamide

Using a procedure substantially similar to that described in Example23-G,2-[2-(3-aminopropoxy)-4-isopropylbenzylamino)]-N-(4-chlorophenyl)pyridine-3-carboxamidewas prepared (0.015 g, 94%) from2-[2-(N-Boc-3-aminopropoxy)-4-isopropylbenzylamino)]-N-(4-chlorophenyl)-pyridine-3-carboxamide.

¹NMR

FD-MS, m/e 453 (m+1)

EXAMPLE 25 Preparation of4-[4-tert-Butyl-2-(piperidin-4-yloxy)benzoyl-amino]-N-(5-chloropyridin-2-yl)pyridine-3-carboxamideTrifluoroacetate

A. 4-(Boc-amino)pyridine

To a stirring solution of 4-aminopyridine (15 g, 159 mmol) andtriethylamine (24 mL, 175 mmol) in DMF (300 mL) was added di-t-butyldicarbonate (38 g, 175 mmol). After stirring overnight, the solvent wasremoved in vacuo. The residue was dissolved in ethyl acetate (500 mL);and the solution was washed with satd aq sodium bicarbonate, water andthen brine. The organic phase was then dried with MgSO₄, filtered andconcentrated in vacuo to a volume of about 100 mL. The mixture was thensonicated and the precipitate was filtered and dried in vacuo to give9.52 g (31%) of the title compound. To the mother liquor was added about50 g of silica gel and the mixture was concentrated in vacuo. Theresulting dry pack was loaded onto a silica gel column prepared with asolution of 50% ethyl acetate in 5 hexanes and eluted with 20% ethylacetate in dichloromethane, followed by a step gradient of 50% ethylacetate in hexanes through ethyl acetate. The product containingfractions were combined and concentrated in vacuo to give another 16.16g (52%) of the title compound.

¹NMR

IS-MS, m/e 195.3 (m+1)

B. 4-(Boc-amino)pyridine-3-carboxylic Acid

To a stirring solution of 4-(Boc-amino)pyridine (1.027 g, 5.30 mmol) inTHF at −36° C. (internal temperature) was added a 1.7 M solution oft-butyl lithium in pentane (6.5 mL, 11 mmol), and the rate of additionwas controlled so as to keep the internal temperature below −28° C.After an additional hour (temperature kept between −30° C. and −50° C.)carbon dioxide (g) was bubbled through the solution and the cold bathwas removed. After about 15 min, the mixture was poured into ice waterand the aqueous phase was washed with dichloromethane. The pH wasadjusted to 4-5 with citric acid, and the resulting precipitate waswashed with dichloromethane and methanol and dried in vacuo to give thetitle compound (0.811 g, 64%) as an off-white solid.

¹NMR

IS-MS, m/e 239.0 (m+1)

Analysis for C₁₁H₁₄N₂O₄:

Calcd: C, 55.46; H, 5.92; N, 11.76;

Found: C, 55.73; H, 6.07; N, 11.75.

C. Methyl 4-(Boc-amino)pyridine-3-carboxylate

To a stirring suspension of 4-(Boc-amino)pyridine-3-carboxylic acid(1.04 g, 4.37 mmol) in methanol (3.5 mL) was added a 2 M solution of(trimethylsilyl)diazomethane in hexanes (3.5 mL, 7 mmol). After 15 min,acetic acid was added and the solvents were removed in vacuo. Theresidue was chromatographed over silica gel, eluting with a stepgradient of 20% ethyl acetate in hexanes through 70% ethyl acetate inhexanes. The product containing fractions were combined and concentratedin vacuo to give the title compound (0.894 g, 81%) as a white solid.

¹NMR

D. Methyl 4-aminopyridine-3-carboxylate

Methyl 4-(Boc-amino)pyridine-3-carboxylate (2.38 g, 9.4 mmol) wasdissolved in TFA (20 mL) and the solution was allowed to stir for 45min. The solvent was removed in vacuo and the residue was partitionedbetween 25% isopropanol in chloroform and satd aq sodium bicarbonate.The layers were separated and the aqueous phase was extracted again with25% isopropanol in chloroform. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo to give a solid which waswashed with diisopropyl ether and dried in vacuo to give the titlecompound (1.327 g, 92%) as an off-white solid.

¹NMR

IS-MS, m/e 153.1 (m+1)

Analysis for C₇H₈N₂O₂:

Calcd: C, 55.26; H, 5.30; N, 18.41;

Found: C, 55.31; H, 5.36; N, 18.42.

E. Methyl4-tert-Butyl-4-[2-(1-Boc-piperidin-4-yloxy)-benzoylamino]pyridine-3-carboxylate

To a stirring suspension of methyl 4-aminopyridine-3-carboxylate (0.10g, 0.659 mmol) in dichloromethane (1 mL) was added a solution of4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride (1.3 mmol) indichloromethane (6 mL), followed by N,N-diisopropylethylamine (0.15 mL,0.8 mmol) and 4-N,N-dimethylaminopyridine (0.0084 g, 0.068 mmol). Afterstirring overnight, the solution was diluted with ethyl acetate andwashed three times with satd aq NaHCO₃. The combined aq phase was backextracted with ethyl acetate and the combined organic phase was driedwith MgSO₄, filtered and concentrated in vacuo. The residue waschromatographed over silica gel, eluting with a gradient of 30% ethylacetate in hexanes through 100% ethyl acetate. The product containingfractions were combined and concentrated in vacuo to give the titlecompound (0.223 g, 66%) as a thick yellow syrup.

¹NMR

IS-MS, m/e 512.3 (m+1)

F.4-[4-tert-Butyl-2-(1-Boc-piperidin-4-yloxy)benzoyl-amino]pyridine-3-carboxylicacid

To a stirring solution of methyl4-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoylamino]pyridine-3-carboxylate(0.192 g, 0.376 mmol) in tetrahydrofuran (4 mL) was added water (1 mL),followed by a 1 M solution of LiOH in water (0.4 mL, 0.4 mmol). Afterstirring overnight, the solution was partially concentrated in vacuo andthen diluted with water and washed with diethyl ether. The pH of the aqphase was then adjusted to 4-5 by the addition of citric acid. Theresulting precipitate was dried in vacuo to give the title compound(0.15 g, 80%) as a white solid.

¹NMR

IS-MS, m/e 508.1 (m+1)

G.2-[4-tert-Butyl-2-(1-Boc-piperidin-4-yloxy)phenyl]-4H-pyrido[4,3-d][1,3]oxazin-4-one

To a stirring solution of4-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoylamino]pyridine-3-carboxylicacid (0.15 g, 0.30 mmol) in DMF (5 mL) was added1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride (0.077 g,0.39 mmol). After stirring overnight, the solvent was removed in vacuoand the residue was dissolved in ethyl acetate and washed twice with icewater/brine. The combined aq phase was back extracted with ethyl acetateand the combined organic phase was dried with MgSO₄, filtered andconcentrated in vacuo to give the title compound (0.121 g, 84%) as alight yellow foam.

¹NMR

H.4-[4-tert-Butyl-2-(1-Boc-piperidin-4-yloxy)benzoyl-amino]-N-(5-chloropyridin-2-yl)pyridine-3-carboxamide

To a stirring solution of 2-amino-5-chloropyridine (0.055 g, 0.42 mmol)in THF (5 mL) at 0° C., was added a 1.0 M solution of allylmagnesiumchloride in diethyl ether (0.4 mL, 0.4 mmol). To this solution was thenadded a solution of2-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)-phenyl]-4H-pyrido[4,3-d][1,3]oxazin-4-one(0.12 g, 0.25 mmol) in THF (3 mL). After several hours, the solution wasdiluted with ethyl acetate and washed twice with brine. The organicphase was then dried with MgSO₄, filtered and concentrated in vacuo togive a white solid which was washed with diethyl ether and dried invacuo to give the title compound (0.11 g, 70%).

¹NMR

IS-MS, m/e 608.2 (m+1)

Analysis for C₃₂H₃₈ClN₅O₅:

Calcd: C, 63.20; H, 6.30; N, 11.52;

Found: C, 63.10; H, 6.39; N, 11.25.

I.4-[4-tert-Butyl-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-3-carboxamidetrifluoroacetate

To a stirring solution of4-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-3-carboxamide(0.099 g, 0.163 mmol) and anisole (0.1 mL) in dichloromethane (5 mL) wasadded TFA (0.5 mL). After 2 h, the solvent was removed in vacuo and theresidue was suspended in toluene and concentrated in vacuo. The residuewas then diluted with diethyl ether and concentrated in vacuo. Finally,the residue was again diluted with diethyl ether with vigorous stirringto yield a solid precipitate, which was filtered and washed with diethylether and dried in vacuum to give the title compound (0.089 g, 88%) as awhite solid.

¹NMR

IS-MS, m/e 508.3 (m+1)

Analysis for C₂₇H₃₀ClN₅O₃.1.9 TFA:

Calcd: C, 51.05; H, 4.44; N, 9.66; F, 14.94;

Found: C, 50.93; H, 4.48; N, 9.44; F, 14.77.

EXAMPLE 26 Preparation ofN-(5-Chloropyridin-2-yl)-3-[4-(2-fluoro-ethoxy)-2-(piperidin-4-yloxy)benzoylamino]pyridine-2-carboxamide

A. Methyl 4-(2-Fluoroethoxy)-2-hydroxybenzoate

A mixture of methyl 2,4-dihydroxybenzoate (5.04 g, 30 mmol),1-bromo-2-fluoroethane (4.18 g, 2.46 mL, 33 mmol), potassium carbonate(4.55 g, 33 mmol) and potassium iodide (1 g) in DMF (20 mL) was heatedovernight at 55-60° C. before it was poured into water (150 mL). Theresulting white precipitate was filtered, redissolved indichloromethane, dried (MgSO₄), concentrated and diluted with hexane toafford the ether in two crops (1.30 g and 2.19 g). The first crop wascharacterized:

EI-MS, 214.03 (m)

Analysis for C₁₀H₁₁FO₄:

Calcd: C, 56.08; H, 5.18;

Found: C, 56.07; H, 5.27.

B. Methyl2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(2-fluoroethoxy)benzoate

Using a procedure similar to that of Example 6-D, methyl4-(2-fluoroethoxy)-2-hydroxybenzoate (3.6 g, 17.8 mmol),1-tert-butoxycarbonyl-4-hydroxypiperidine (3.58 g, 17.8 mmol), andtriphenylphosphine (5.60 g, 21.4 mmol) in THF (75 mL) is treated withdiethyl azodicarboxylate (3.60 g, 17.8 mmol) in THF (15 mL) to affordthe crude product (7.28 g) which is used without further purification.

C. 2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(2-fluoroethoxy)benzoicAcid

Using a procedure similar to that of Example 6-E, methyl2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-fluoroethoxy)benzoate(7.28 g) is hydrolyzed using LiOH.H₂O (1.78 g, 2.2 equivalents), water(20 mL) and THF (60 mL) at 60-65° C. to afford the acid (2.76 g, 40%).

D.N-(5-Chloropyridin-2-yl)-3-[4-(2-fluoroethoxy)-2-(piperidin-4-yloxy)benzoylamino]pyridine-2-carboxamide

Using a procedure similar to that of Example 1-I,2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-fluoro-ethoxy)benzoicacid (0.767 g, 2 mmol) is treated with oxalyl chloride (0.193 mL, 2.2mmol) and pyridine (1.78 mL, 22 mmol) in dichloromethane (50 mL) toafford the acid chloride.

The acid chloride in dichloromethane (25 mL) is cooled in an ice bathand treated with 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.465 g, 2 mmol) in dichloro-methane (25 mL) and allowed to warm toroom temperature overnight to afford3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-fluoroethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide.

The concentrated crude amide is taken up in ethyl acetate andpartitioned into water by the addition of 5 N HCl and hexane. The acidicaqueous phase is separated and basified with aqueous potassium carbonateto afford a precipitate. The precipitate is collected, washed with waterand dried under vacuum to provide the title compound (0.286 g).

EXAMPLE 27 Preparation ofN-(5-Chloropyridin-2-yl)-3-[4-(2-fluoro-ethoxy)-2-(piperidin-3-ylmethoxyoxy)benzoylamino]pyridine-2-carboxamide

A.2-(1-tert-Butoxycarbonylpiperidin-3-ylmethoxy)-4-(2-fluoroethoxy)benzoicAcid

Using a procedure similar to that of Example 26-B,4-(2-fluoroethoxy)-2-hydroxybenzoate (2.6 g, 12.8 mmol),1-tert-butoxycarbonylpiperidin-3-ylmethanol (2.76 g, 12.8 mmol), andtriphenylphosphine (4.02 g, 15.4 mmol) in THF (50 mL) is treated withdiethyl azodicarboxylate (2.59 g, 12.8 mmol) in THF to afford methyl2-(1-tert-butoxycarbonyl-piperidin-3-ylmethoxy)-4-(2-fluoroethoxy)benzoate(6.35 g) which is used without further purification.

Using a procedure similar to that of Example 26-C, the ester ishydrolyzed using LiOH.H₂O (1.50 g, 2.2 equivalents), water (20 mL) andTHF (60 mL) to afford the acid (2.93 g, 59% for the two steps).

B.N-(5-Chloropyridin-2-yl)-3-[4-(2-fluoroethoxy)-2-(piperidin-3-ylmethoxy)benzoylamino]pyridine-2-carboxamide

Using a procedure similar to that of Example 26-D,2-(1-tert-butoxycarbonylpiperidin-3-ylmethoxy)-4-(2-fluoro-ethoxy)benzoicacid (0.767 g, 2 mmol) is converted into the acid chloride.

Using a procedure similar to that of Example 26-D, the acid chloride istreated with 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.465 g, 2 mmol). The crude reaction mixture is shaken with cold 2 NHCl; and the resulting organic phase was washed with aqueous potassiumcarbonate, dried (MgSO₄) and evaporated to afford3-[2-(1-tert-butoxycarbonylpiperidin-3-ymethoxy)-4-(2-fluoroethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamidewhich is used without further purification.

The above amide in dichloromethane (5 mL) is treated with TFA (5 mL) for5 h at room temperature. After evaporation, the resulting solid istriturated with hexane, and precipitated with ethyl ether-hexane. Theresulting solid is redissolved in ethyl acetate and partitioned into 5 NHCl, with addition of hexane to the organic phase. The The acidicaqueous phase is separated, basified with aqueous potassium carbonate,and extracted with ethyl acetate. The organic phase is dried (MgSO₄) andevaporated to a solid which is crystallized from dichloromethane-hexaneto provide the title compound (0.169 g, 16% overall).

¹NMR

MS

EXAMPLE 28 Preparation of3-[2-(3-Amino-2,2-dimethylpropoxy)-4-(2-fluoroethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamideBis(trifluoroacetate)

A.2-(3-tert-Butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-fluoroethoxy)benzoicAcid

Using a procedure similar to that of Example 26-B, methyl4-(2-fluoroethoxy)-2-hydroxybenzoate (3.6 g, 17.8 mmol) is alkylatedwith 3-tert-butoxycarbonylamino-2,2-dimethylpropanol (3.62 g, 17.8 mmol)to afford methyl2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-fluoroethoxy)benzoate(5.12 g).

Using a procedure similar to that of Example 26-C, the ester (5.12 g) ishydrolyzed to afford the acid (2.44 g, 34% for the two steps).

B.3-[2-(3-Amino-2,2-dimethylpropoxy)-4-(2-fluoroethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

Using a procedure similar to that of Example 26-D,2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-fluoroethoxy)benzoicacid (0.798 g, 2 mmol) is converted into the acid chloride.

Using a procedure similar to those of Examples 1-1 and 26-D, the acidchloride is treated with3-amino-N-(5-chloro-pyridin-2-yl)pyridine-2-carboxamide (0.465 g, 2mmol) to afford3-[2-(3-tert-butoxycarbonylamino-2,2-dimethyl-propoxy)-4-(2-fluoroethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.320 g, 27%) after purification by elution from silica gel.

Using a procedure similar to that of Example 1-J, the above compound wastreated with 1:1 TFA:dichloromethane, to afford, after evaporation, thetitle compound as the bis(trifluoroacetate) salt (0.260 g, 67%).

¹NMR

MS

EXAMPLE 29 Preparation of3-[2-(cis-4-Aminocyclohexyloxy)-4-(2-fluoro-ethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTris(trifluoroacetate)

A.2-(cis-4-tert-Butoxycarbonylaminocyclohexyloxy)-4-(2-fluoroethoxy)benzoicAcid

Using a procedure similar to that of Example 6-D, methyl4-(2-fluoroethoxy)-2-hydroxybenzoate (5.0 g, 24.75 mmol),trans-4-tert-butoxycarbonylaminocyclohexanol (5.02 g, 24.75 mmol), andtriphenylphosphine (1.2 equivalents) in THF (125 mL) is treated withdiethyl azodicarboxylate (1.3 equivalents) in THF (25 mL). After havingstirred overnight at room temperature, the reaction mixture was heated 8h at 40-50° C., then stirred overnight at room temperature. The crudeproduct was isolated by elution from silica gel with a gradient of 0 to40% ethyl acetate in hexane to afford crude methyl2-(cis-4-tert-butoxycarbonylaminocyclohexyloxy)-4-(2-fluoroethoxy)benzoate(7.30 g), which is used without further purification.

Using a procedure similar to that of Example 26-C, the above crude ester(7.30 g) is hydrolyzed to afford the acid (0.87 g, 8.8%), which is usedwithout further purification.

B.3-[2-(cis-4-Aminocyclohexyloxy)-4-(2-fluoroethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

Using a procedure similar to that of Example 26-D,3-[2-(cis-4-tert-butoxycarbonylaminocyclohexyloxy)-4-(2-fluoroethoxy)benzoicacid (0.87 g, 2.19 mmol) is converted into the acid chloride.

Using a procedure similar to that of Example 26-D, the acid chloride istreated with 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.510 g, 2.19 mmol) to afford3-[2-(cis-4-tert-butoxycarbonylaminocyclohexyloxy)-4-(2-fluoroethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide(0.415 g, 30%).

Using a procedure similar to that of Example 1-J, the above compound wastreated with 1:1 TFA:dichloromethane (3 mL each), to afford, afterfiltration of some insoluble material and evaporation, the titlecompound as the tris(trifluoroacetate) salt (0.374 g, 73%).

EXAMPLE 30 Preparation of3-[2-(3-Aminopropoxy)-4-(2-fluoroethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide

A. 2-(3-tert-Butoxycarbonylaminopropoxy)-4-(2-fluoro-ethoxy)benzoic Acid

Using a procedure similar to that of Example 6-D, methyl4-(2-fluoroethoxy)-2-hydroxybenzoate (5.0 g, 24.75 mmol)-,3-tert-butoxycarbonylaminopropanol (4.13 mL, 24.75 mmol), andtriphenylphosphine (1.2 equivalents) in THF (125 mL) is treated withdiethyl azodicarboxylate (1.3 equivalents) in THF (25 mL). The crudeproduct is isolated by elution from silica gel with a gradient of 0 to40% ethyl acetate in hexane to afford methyl2-(3-tert-butoxycarbonyl-aminopropoxy)-4-(2-fluoroethoxy)benzoic acid(6.18 g), which is used without further purification.

The above ester is hydrolyzed using LiOH.H₂O (6.99 g, 10 equivalents),water (10 mL) and THF (30 mL) by heating the reaction mixture 18 h at65° C. After evaporation of the organic solvent, the residue is dilutedwith water (200 mL) and partitioned with a mixture of ethyl acetate (150mL) and hexane (100 mL). The aqueous phase is acidified and then madebasic with aqueous potassium carbonate during the partitioning. Theresulting basic aqueous phase is washed with 1:1 ethyl acetate:hexane(250 mL), acidified with 5 N HCl, and extracted with ethyl acetate. Theethyl acetate solution is dried (MgSO₄) and evaporated to afford theacid (3.89 g, 44%) as a solid.

B.3-[2-(3-Aminopropoxy)-4-(2-fluoroethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

Using a procedure similar to that of Example 26-D,2-(3-tert-butoxycarbonylaminopropoxy)-4-(2-fluoroethoxy)-benzoic acid(1.43 g, 4 mmol) is converted into the acid chloride.

Using a procedure similar to that of Example 26-D, the acid chloride istreated with 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.931 g, 4 mmol). The reaction mixture is diluted with dichloromethaneand washed with cold water. Evaporation, followed by isolation of thecrude product from silica gel, eluting with a gradient of 0-40% ethylacetate in hexane, and crystallization from dichloromethane-hexaneaffords a first crop of3-[2-(3-tert-butoxycarbonylaminopropoxy)-4-(2-fluoroethoxy)benzoyl-amino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.325 g). Chromatography of the mother liquor provides a further 0.110g of amide (0.435 g, 15.5% for two steps).

Using a procedure similar to that of Example 1-J, the above compound(0.4 g) was treated with 1:1 TFA:dichloro-methane (2 mL each), to affordthe bis(trifluoroacetate) salt (0.378 g).

C.3-[2-(3-Aminopropoxy)-4-(2-fluoroethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide

The above salt was converted into the free base using potassiumcarbonate solution and ether. The title compound (0.07 g, 19.4%) wasobtained by evaporation and crystallization from dichloromethane-hexane.

EXAMPLE 31 Preparation ofN-(5-Chloropyridin-2-yl)-3-[2-(piperidin-4-yloxy)-4-(2,2,2-trifluoroethoxy)-benzoylamino]pyridine-2-carboxamideBis(Trifluoroacetate)

A. Methyl 2-Hydroxy-4-(2,2,2-trifluoroethoxy)benzoate

A solution of methyl 2,4-dihydroxybenzoate (5.04 g, 30 mmol) inhexamethylphosphorous triamide (HMPT, 30 mL) under nitrogen was treatedwith sodium hydride (50% suspension, 1.44 g, 30 mmol) to form thephenolate salt before the addition of 2,2,2-trifluoroethylmethanesulfonate (4.24 mL, 36 mmol). The reaction mixture was heatedovernight at 140° C. before it was poured into brine (300 mL). Theresulting mixture was extracted with ethyl acetate (200 mL); and theorganic phase was washed with water (300 mL), dried (MgSO₄) andevaporated. The residue was purified by HPLC over silica gel, elutingwith a gradient of 0-30% ethyl acetate in hexane. The product containingfractions were variously combined and concentrated beforecrystallization from dichloromethane-hexane (or, for the mother liquors,from hexane) to provide the ether in several crops as a solid (2.12 g,28%).

B.2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(2,2,2-trifluoroethoxy)benzoicAcid

Using a procedure similar to that of Example 26-B, methyl2-hydroxy-4-(2,2,2-trifluoroethoxy)benzoate (2.0 g, 7.99 mmol) isalkylated with 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.61 g, 7.99mmol) to afford methyl2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2,2,2-trifluoroethoxy)benzoate(2.86 g).

Using a procedure similar to that of Example 26-C, the ester (2.86 g) ishydrolyzed to afford the acid (1.43 g, 43% for the two steps).

C.N-(5-Chloropyridin-2-yl)-3-[2-(piperidin-4-yloxy)-4-(2,2,2-trifluoroethoxy)-benzoylamino]pyridine-2-carboxamideTrifluoroacetate

Using a procedure similar to that of Example 26-D,2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2,2,2-trifluoroethoxy)benzoicacid (0.75 g, 1.79 mmol) is converted into the acid chloride.

Using a procedure similar to that of Example 26-D, the acid chloride istreated with 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.416 g, 1.79 mmol) to afford3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2,2,2-trifluoroethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.407 g, 35% for two steps) after crystallization fromdichloromethane-hexane.

Using a procedure similar to that of Example 1-J, the above compound wastreated with 1:1 TFA:dichloromethane (4 mL each), to afford, afterfiltration of some insoluble material and evaporation, the titlecompound as the bis(trifluoroacetate) salt (0.386 g, 28%).

¹NMR

MS

EXAMPLE 32 Preparation ofN-(5-Chloropyridin-2-yl)-3-[4-(2-methoxy-ethoxy)-2-(piperidin-4-yloxy)benzoylamino]pyridine-2-carboxamideBis(trifluoroacetate)

A. Methyl 2-Hydroxy-4-(2-methoxyethoxy)benzoate

A mixture of methyl 2,4-dihydroxybenzoate (5.04 g, 30 mmol),1-bromo-2-methoxyethane (3.1 mL, 33 mmol), potassium carbonate (4.55 g,33 mmol) and sodium iodide (1 g) in DMF (20 mL) was heated overnight at55-60° C. before it was poured into brine (300 mL). The resultingmixture was extracted with ethyl acetate; and the ethyl acetate solutionwas washed with brine, dried (MgSO₄) and evaporated to a residue (6.17g), which was subjected to preparative HPLC over silica gel, elutingwith a gradient of 0-30% ethyl acetate in hexane over 30 min (at 100mL/min), to afford the ether (2.72 g).

B. 2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(2-methoxyethoxy)benzoicAcid

Using a procedure similar to that of Example 26-B, methyl2-hydroxy-4-(2-methoxyethoxy)benzoate (2.72 g, 12.02 mmol) is alkylatedwith 1-tert-butoxycarbonyl-4-hydroxy-piperidine (2.44 g, 12.02 mmol) toafford methyl2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-methoxyethoxy)benzoate(4.41 g).

Using a procedure similar to that of Example 26-C, the ester (4.41 g) ishydrolyzed to afford the acid (2.03 g).

C.N-(5-Chloropyridin-2-yl)-3-[4-(2-methoxyethoxy)-2-(piperidin-4-yloxy)benzoylamino]pyridine-2-carboxamideTrifluoroacetate

Using a procedure similar to that of Example 26-D,2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-methoxy-ethoxy)benzoicacid (0.818 g, 2.0 mmol) is, converted into the acid chloride.

Using a procedure similar to that of Example 26-D, the acid chloride istreated with 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.465 g, 2.0 mmol) to afford3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-methoxy-ethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.435 g) as the first crop after crystallization.

Using a procedure similar to that of Example 1-J, the above compound wastreated with 1:1 TFA:dichloromethane (4 mL each), to afford, afterfiltration of some insoluble material and evaporation, the titlecompound as the bis(trifluoroacetate) salt (0.361 g).

¹NMR

EXAMPLE 33 Preparation of3-[2-(cis-4-Aminocyclohexyloxy)-4-(2-methoxy-ethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTris(trifluoroacetate)

A.2-(cis-4-tert-Butoxycarbonylaminocyclohexyloxy)-4-(2-methoxyethoxy)benzoicAcid

Using a procedure similar to that of Example 29-A, methyl2-hydroxy-4-(2-methoxyethoxy)benzoate (6.0 g, 26.52 mmol) is alkylatedwith trans-4-tert-butoxycarbonylamino-cyclohexanol (5.38 g, 26.52 mmol)to afford the ether (2.70 g), which is used without furtherpurification.

Using a procedure similar to that of Example 29-A, the above crude ester(2.7 g) is hydrolyzed to afford the acid (0.96 g), which is used withoutfurther purification.

B.3-[2-(cis-4-Aminocyclohexyloxy)-4-(2-methoxyethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

Using a procedure similar to that of Example 26-D,2-(cis-4-tert-butoxycarbonylaminocyclohexyloxy)-4-(2-methoxyethoxy)benzoicacid (6.96 g, 2.35 mmol) is converted into the acid chloride.

Using a procedure similar to that of Example 26-D, the acid chloride istreated with 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.547 g, 2.35 mmol) to afford3-[2-(cis-4-tert-butoxycarbonylaminocyclohexyloxy)-4-(2-methoxyethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide(0.210 g) after chromatography over silica gel, eluting with a gradientof 0-50% ethyl acetate in hexane.

Using a procedure similar to that of Example 1-J, the above compound wastreated with 1:1 TFA:dichloromethane (3 mL each), to afford, afterfiltration of some insoluble material and evaporation, the titlecompound as the tris(trifluoroacetate) salt (0.153 g).

EXAMPLE 34 Preparation of3-[2-(3-Amino-2,2-dimethylpropoxy)-4-(2-methoxyethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamideBis(trifluoroacetate)

A.2-(3-tert-Butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-methoxyethoxy)benzoicAcid

Using a procedure similar to that of Example 26-B, methyl2-hydroxy-4-(2-methoxyethoxy)benzoate (3.2 g, 14.14 mmol) is alkylatedwith 3-tert-butoxycarbonylamino-2,2-dimethylpropanol (2.88 g, 14.14mmol) to afford methyl2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-methoxyethoxy)benzoate(4.982 g) after purification over silica gel, eluting with a gradient of0-40% ethyl acetate in hexane.

Using a procedure similar to that of Example 26-C, the ester (4.98 g) ishydrolyzed to afford the acid (1.28 g).

B.3-[2-(3-Amino-2,2-dimethylpropoxy)-4-(2-methoxy-ethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

Using a procedure similar to that of Example 26-D,2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-methoxyethoxy)benzoicacid (1.2 g, 3.02 mmol) is converted into the acid chloride.

Using a procedure similar to that of Example 26-D, the acid chloride istreated with 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.703 g, 3.02 mmol). The reaction mixture is diluted withdichloromethane and partitioned between cold water and a mixture ofethyl acetate and hexane with the aqueous layer being acidified with amixture of 5 N HCl and ice. The separated aqueous layer is basified withaqueous potassium carbonate and washed with ethyl acetate before it isacidified with ice cold 5 N HCl and extracted with ethyl acetate. Theorganic phase is washed with water, dried (MgSO₄), and evaporated. Theproduct is isolated by elution from silica gel, using a gradient of 0 to50% ethyl acetate, to provide3-[2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-methoxy-ethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.11 g).

Using a procedure similar to that of Example 1-J, the above compound istreated with 1:1 TFA:dichloromethane (2 mL each) for 5 h, to afford thetitle compound as the bis(trifluoroacetate) salt (0.070 g).

EXAMPLE 35 Preparation of3-[2-(3-Aminopropoxy)-4-(2-methoxyethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideBis(trifluoroacetate)

A. 2-(3-tert-Butoxycarbonylaminopropoxy)-4-(2-methoxy-ethoxy)benzoicAcid

Using a procedure similar to that of Example 26-B, methyl2-hydroxy-4-(2-methoxyethoxy)benzoate (7.47 g, 33.1 mmol) is alkylatedwith 3-tert-butoxycarbonylaminopropanol (5.51 mL, 33.1 mmol) to affordmethyl2-(3-tert-butoxy-carbonylaminopropoxy)-4-(2-methoxyethoxy)benzoate intwo crude portions (4.35 g and 10.56 g) after purification over silicagel, eluting with a gradient of 0-60% ethyl acetate in hexane.

Using a procedure similar to that of Example 30-A, the ester in twocrude portions (4.35 g and 10.56 g) is hydrolyzed to afford the acid,obtained in several portions (0.28 g and 3.89 g; 0.73 g).

B.3-[2-(3-Aminopropoxy)-4-(2-methoxyethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

Using a procedure similar to that of Example 26-D,2-(3-tert-butoxycarbonylaminopropoxy)-4-(2-methoxy-ethoxy)benzoic acid(1.48 g, 4.0 mmol) is converted into the acid chloride.

Using a procedure similar to that of Example 34-B, the acid chloride istreated with 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.931 g, 4.0 mmol). Isolation of the product from silica gel, elutingwith a gradient of 0-40% ethyl acetate in hexane, affords3-[2-(3-tert-butoxycarbonylaminopropoxy)-4-(2-methoxyethoxy)benzoyl-amino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.30 g).

Using a procedure similar to that of Example 1-J, the above compound istreated with 1:1 TFA:dichloromethane (2 mL each) for 5 h, to afford thetitle compound as the bis(trifluoroacetate) salt (0.278 g).

EXAMPLE 36 Preparation of3-[4-Acetyl-2-(3-aminopropoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

A. 4-(2-Methyl-1,3-dioxolan-2-yl)-2-(methoxymethoxy)-benzoic Acid

To a solution of methoxymethyl 3-(2-methyl-1,3-dioxolan-2-yl)phenylether (8.16 g, 36.4 mmol) in ether (200 mL) was added dropwisetert-butyl lithium (1.7 M solution, 26.8 mL, 1.25 equivalents) at −5 to−10° C. The reaction mixture was stirred 15 min before carbon dioxidegas was bubbled in for 5 min. The reaction mixture was allowed to warmslowly in the cold bath to about 10° C., then it was extracted withwater. The aqueous layer was acidified with 5 N HCl and extracted withEtOAc. The organic phase was dried (MgSO₄) and evaporated to afford acrude product which was triturated with hexane to afford the benzoicacid (4.54 g).

B.N-(5-Chloropyridin-2-yl)-3-[4-(2-methyl-1,3-dioxolan-2-yl)-2-(methoxymethoxy)benzoylamino]pyridine-2-carboxamide

Using a procedure similar to that of Example 26-D,4-(2-methyl-1,3-dioxolan-2-yl)-2-(methoxymethoxy)benzoic acid (4.54 g,16.9 mmol) is treated with oxalyl chloride (1.48 mL, 16.9 mmol) andpyridine (1.37 mL, 16.9 mmol) in dichloromethane (150 mL) to afford theacid chloride.

The acid chloride in dichloromethane (50 mL) is treated with3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (4.20 g, 16.9mmol) And pyridine (2.73 mL, 2×16.9 mL) in dichloromethane (50 mL).After filtration of some insoluble material from the reaction mixture(with washing with dichloromethane), the organic solution is washed with1 N HCl, cold 2 N NaOH, cold dilute HCl, and satd NaHCO₃ before it isdried and evaporated to a crude product (3.10 g), which is used directlywithout further purification.

C.3-[4-Acetyl-2-hydroxybenzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide

N-(5-Chloropyridin-2-yl)-3-[4-(2-methyl-1,3-dioxolan-2-yl)-2-(methoxymethoxy)benzoylamino]pyridine-2-carboxamide(3.10 g) is treated with a solution of TFA (20 mL) and water (20 mL) for2 h before the solution is evaporated. The residue is slurried withethyl acetate to provide a solid which is collected and washed. Thesolid is dispersed in ethyl acetate and extracted with a mixture ofaqueous potassium carbonate and 1 N NaOH. The resulting organic phase iswashed with very dilute HCl, dried and evaporated to afford the productas a solid (0.476 g), which is used directly without furtherpurification.

D.3-[4-Acetyl-2-(3-tert-butoxycarbonylaminopropoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide

A solution of3-[4-acetyl-2-hydroxybenzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.410 g, 1 mmol), 3-(tert-butoxycarbonylamino)propyl bromide (0.286 g,1.2 mmol) and a dash of potassium iodide in DMF (30 mL) is treated withsodium hydride (60%, 44.0 mg, 1.1 mmol) and heated overnight at 70° C.The reaction mixture is cooled and portioned between 0.1 N HCl (150 mL)and ethyl acetate (150 mL). The organic phase is washed with satdNaHCO₃, dried (MgSO₄) and evaporated to a crude product (0.518 g) whichis purified by flash chromatography (silica gel: gradient, 35:1 to 19:1dichloromethane:methanol) to provide the protected amine (0.295 g, 0.050g).

E.3-[4-Acetyl-2-(3-aminopropoxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamideTrifluoroacetate

3-[4-Acetyl-2-(3-tert-butoxycarbonylaminopropoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide(0.345 g) in dichloromethane (4 mL) is treated with TFA (4 mL) for 4 h.The reaction mixture is evaporated, and the residue is triturated twicewith hexane. The solid residue is transferred to a small flask bydissolving it in methanol and evaporation to a solid which is trituratedwith ethyl acetate and hexane to provide the salt as a solid (139 mg).

The methoxymethyl 3-(2-methyl-1,3-dioxolan-2-yl)phenyl ether used as astarting material in Part A, above, may be prepared as follows:

F. 3-(Acetyl)phenyl Methoxymethyl Ether

To a stirred solution of 3-hydroxyacetophenone (20.40 g, 150 mmol) inCH₂Cl₂ (450 mL) at 0° C. under N₂ was added N,N-diisopropylethylamine(52.25 mL, 300 mmol) followed by methyl chloromethyl ether (MOMchloride) (13.67 mL, 180 mmol) over a period of 30 min. The reaction wasstirred at 0° C. for 30 min and then at room temperature for 2 h. Thereaction was quenched with H₂O (500 mL). The organic solution wasseparated, washed with H₂O (2×500 mL), 0.5 N NaOH (2×100 mL), and againwith H₂O (200 mL). The organic solution was dried (Na₂SO₄) andconcentrated. The resulting residue was purified by filtration through apad of silica gel using n-hexanes through 2-5% EtOAc/n-hexanes to givethe desired product (17.30 g, 64%); TLC Rf: 0.45 (20% EtOAc/n-hexanes).

¹H NMR (400 MHz, CDCl₃): δ 7.62(dd, 1H, J=1.6 and 8.4 Hz); 7.59(d, 1H,J=1.6 Hz); 7.38(t, 1H, J=6 Hz); 5.23(s, 2H); 3.49(s, 3H); 2.60(s, 3H).

IS-MS (m/e): 180 (m)

Analysis for C₁₀H₁₂O₃:

Calcd: C, 66.65; H, 6.71;

Found: C, 67.73; H, 6.87.

G. Methoxymethyl 3-(2-methyl-1,3-dioxolan-2-yl)phenyl Ether

A mixture of 3-(acetyl)phenyl methoxymethyl ether (3.6 g, 20 mmol),ethylene glycol (3.72 g, 60 mmol) and pyridinium tosylate (0.075 g, 0.3mmol, 3 mol %) in benzene (200 mL) was azeotropically refluxed for 8 h.The reaction was concentrated and the resulting residue was diluted withethyl ether (150 mL) and washed with saturated aqueous bicarbonate (2×50mL) and brine (100 mL). The ethyl ether solution was dried (K₂CO₃) andconcentrated. The residue was suspended in n-hexanes and the by-productwas precipitated. The n-hexane solution was then separated andconcentrated to obtain the desired product (2.69 g, 61%); TLC Rf: 0.5(30% EtOAc/n-hexanes).

¹H NMR (400 MHz, CDCl₃): δ 7.33(t, 1H, J=7.6 Hz); 7.22(ddd, 1H, J=1.6,2.4 and 7.6 Hz); 7.19(bs, 1H); 7.06(dd, 1H, J=1.2 and 8.0 Hz); 5.26(s,2H); 4.10(m, 2H); 3.86(m, 2H); 3.56(s, 3H); 1.73(s, 3H).

IS-MS (m/e): 225 (m+1)

Analysis for C₁₂H₁₆O₄:

Calcd: C, 64.27; H, 7.19;

Found: C, 64.46; H, 7.09.

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein: A³, A⁴, A⁵ andA⁶, together with the two carbons to which they are attached, complete asubstituted heteroaromatic ring in which one of A³, A⁴, A⁵ and A⁶ is N,and each of the others is CR³, CR⁴, CR⁵ or CR⁶, respectively; whereineach of R³, R⁴, R⁵ and R⁶ is hydrogen; or one or more of R³, R⁴, R⁵ andR⁶ is methyl each of the others is hydrogen; or one of R³, R⁴, R⁵ and R⁶attached to a carbon which is not bonded to an N-atom is chloro and eachof the others are hydrogen; or two adjacent residues of A³, A⁴, A⁵ andA⁶ together form S, and each of the others is CH; L is carbonyl ormethylene; R is 2-pyridinyl (which may bear a methyl, cyano, carbamoyl,hydroxymethyl, formyl, vinyl, amino, hydroxy, methoxy, difluoromethoxy,methylthio, fluoro or chloro substituent at the 5-position), or R is3-pyridinyl (which may bear a methyl, fluoro or chloro substituent atthe 6-position), or R is 2-thiazolyl (which may bear a methylsubstituent at the 4-position or a bromo substituent at the 5-position),or R is phenyl (which may bear one, two or three substituents at the 3-,4- or 5-position(s) independently selected from fluoro, chloro, bromo,cyano, carbamoyl, methyl, methoxy, difluoromethoxy, hydroxymethyl,formyl, vinyl, amino, hydroxy and 3,4-methylenedioxy; and in additionthe phenyl may bear a 2-chloro or 2-fluoro substituent), or R is6-indolyl (which may bear a chloro or methyl substituent at the3-position); R¹ is —(CH₂)_(i)-Q-(CH₂)_(j)—NR^(a)R^(b) in which a) Q is asingle bond; the sum of i and j is 2 or 3; and each of R^(a) and R^(b)is hydrogen, or each of R^(a) and R^(b) is independently (1-3C) normalalkyl, or R^(a) is hydrogen and R^(b) is (1-3C)alkyl or formyl, orNR^(a)R^(b) is 1-pyrrolidinyl or 4-morpholinyl; b) Q is —CH(CH₃)—,—C(CH₃)₂— or —CH(OH)—; each of i and j is 1; and each of R^(a) and R^(b)is hydrogen, or each of R^(a) and R^(b) is independently (1-3C) normalalkyl, or R^(a) is hydrogen and R^(b) is (1-3C)alkyl or formyl, or—NR^(a)R^(b) is 1-pyrrolidinyl or 4-morpholinyl; c) Q iscyclohexane-1,4-diyl; each of i and j is 0; R^(a) is hydrogen; and R^(b)is hydrogen or methyl; d) Q is —CHR^(c)—; i is 0; j is 1; R^(a) ishydrogen or methyl; and R^(b) and R^(c) together are —(CH₂)_(k)— whereink is 2 or 3; e) Q is —CHR^(c)—; i is 1; j is 1; R^(a) is hydrogen ormethyl; and R^(b) and R^(c) together are —(CH₂)_(k)— wherein k is 1, 2or 3; or f) Q is —CHR^(c)—; i is 0 or 1; j is 2; R^(a) is hydrogen ormethyl; and R^(b) and R^(c) together are —(CH₂)_(k)— wherein k is 2; andR² is fluoro, chloro, (1-4C)alkyl, —NR^(d)R^(e), —OR^(f), acetyl,—CONR^(g)R^(h) or NHCOR^(i) in which each of R^(d) and R^(e) isindependently hydrogen or (1-3C)alkyl; or —NR^(d)R^(e) is1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl,hexahydro-1,4-diazepin-1-yl or 4-morpholinyl (in which the 1-piperazinylor hexahydro-1,4-diazepin-1-yl may bear a 4-methyl substituent and the1-piperidinyl may bear one or two 4-methyl substituents); R^(f) is(1-3C)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or 2-methoxyethyl; eachof R^(g) and R^(h) is hydrogen, or R^(g) is hydrogen and R^(h) is(1-6C)alkyl or (3-6C)cycloalkyl, or each of R^(g) and R^(h) isindependently (1-3C)alkyl, or —NR^(g)R^(h) is 1-pyrrolidinyl,1-piperidinyl, 1-piperazinyl or 4-morpholinyl (in which the1-piperazinyl may bear a 4-methyl substituent and the 1-piperidinyl maybear one or two 4-methyl substituents); and R^(i) is hydrogen,(1-6C)alkyl or (3-6C)cycloalkyl.
 2. The compound or salt of claim 1wherein R is 2-pyridinyl, which bears a methyl, fluoro or chlorosubstituent at the 5-position; or R is 2-thiazolyl, which may bear amethyl substituent at the 4-position or a bromo substituent at the5-position, or R is phenyl, which may bear a fluoro, chloro or methoxysubstituent at the 4-position; or R is 6-indolyl; R¹ is 2-aminoethyl,2-(dimethylamino)ethyl, 2-(formylamino)ethyl, 3-aminopropyl,3-(formylamino)propyl, 3-(1-pyrrolidinyl)propyl,3-(4-morpholinyl)propyl, 3-amino-2-methylpropyl,3-amino-2,2-dimethylpropyl, 3-amino-2-hydroxypropyl,cis-4-aminocyclohexyl, cis-4-(methylamino)-cyclohexyl, 3-pyrrolidinyl,3-piperidinyl, 3-azetidinyl-methyl, 3-pyrrolidinylmethyl,3-piperidinylmethyl, 4-piperidinyl, 4-piperidinylmethyl or1-methyl-piperidin-4-yl; and R² is fluoro, isopropyl, tert-butyl,dimethylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl,hexahydro-1,4-diazepin-1-yl, 4-morpholinyl, methoxy, ethoxy,2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethoxy or acetyl.
 3. Thecompound or salt of claim 2 wherein R is 5-chloropyridin-2-yl,2-thiazolyl, 4-methylthiazol-2-yl, 5-bromothiazol-2-yl or4-chlorophenyl; R¹ is 2-aminoethyl, 2-(formylamino)ethyl,3-amino-propyl, 3-(formylamino)propyl, 3-amino-2,2-dimethylpropyl,cis-4-aminocyclohexyl, 3-piperidinylmethyl or 4-piperidinyl; and R² isfluoro, isopropyl, tert-butyl, dimethylamino, 1-pyrrolidinyl,4-morpholinyl, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethoxy oracetyl.
 4. The compound or salt of claim 3 wherein R is5-chloropyridin-2-yl; R¹ is 3-amino-2,2-dimethylpropyl,cis-4-amino-cyclohexyl, or 4-piperidinyl; and R² is 1-pyrrolidinyl,4-morpholinyl, 2-fluoroethoxy or 2-methoxyethoxy.
 5. The compound orsalt of any one of claims 1-4 wherein one of A³, A⁴, A⁵ and A⁶ is N, andeach of the others is CR³, CR⁴, CR⁵ or CR⁶, respectively; in which eachof R³, R⁴ and R⁶ is hydrogen and R⁵ is hydrogen or methyl.
 6. Thecompound or salt of claim 5 wherein each of R³, R⁴, R⁵ and R⁶ ishydrogen.
 7. The compound or salt of claim 5 or 6 wherein A³ is N. 8.The compound or salt of claim 5 or 6 wherein A⁴ is N.
 9. The compound orsalt of claim 5 or 6 wherein A⁵ is N.
 10. The compound or salt of claim5 or 6 wherein A⁶ is N.
 11. The compound or salt of any one of claims1-4 wherein A³, A⁴, A⁵ and A⁶, together with the two carbons to whichthey are attached, complete a substituted thiophene ring in which (a) A³and A⁶ are each CH; or (b) A³ and A⁴ are each CH.
 12. The compound orsalt of any one of claims 1-11 wherein L is carbonyl.
 13. The compoundor salt of any one of claims 1-11 wherein L is methylene.
 14. Thecompound of claim 1 which is: (a)N-(5-chloropyridin-2-yl)-3-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxamide;(b)4-[4-tert-butyl-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-3-carboxamide;or (c)3-[2-(cis-4-Aminocyclohexyloxy)-4-(2-fluoroethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 15. (canceled)
 16. Apharmaceutical composition comprising in association with apharmaceutically acceptable carrier, diluent or excipient, a compound offormula I, or a pharmaceutically acceptable salt thereof, as provided inclaim
 1. 17. (canceled)
 18. (canceled)
 19. A method of treating athromboembolic disorder in a mammal in need of treatment comprisingadministering to the mammal an effective amount of a compound of formulaI, or pharmaceutically acceptable salt thereof, as described in claim 1.20. A process for preparing a compound of formula I, or apharmaceutically acceptable salt thereof, as provided in claim 1comprising the step selected from (A) for a compound in which L iscarbonyl, acylating an amine of formula II,

using an acid of formula III (in which R^(a) as hydrogen may be replacedby a nitrogen protecting group R^(p)),

or an activated derivative thereof; (B) acylating an amine of formulaR—NH₂ using an acid of formula IV (in which R^(a) as hydrogen may bereplaced by a nitrogen protecting group R^(p)),

or an activated derivative thereof; (C) for a compound of formula I inwhich L is methylene, substituting the group Y^(a) of a compound offormula VI

in which Y^(a) is a leaving group for nucleophilic aromatic substitutionwith an amine of formula VII

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p)); or alkylating an amine of formula II directly, using acompound of formula VIII,

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p)) in which Y^(b) is a leaving group for nucleophilicsubstitution, or indirectly, by reductive alkylation using an aldehydeof formula IX;

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p)); (D) for a compound of formula I in which each of R^(a) andR^(b) is (1-3C) normal alkyl, or R^(a) is hydrogen and R^(b) is methylor (1-3C)alkyl, or NR^(a)R^(b) is 1-pyrrolidinyl or 4-morpholinyl,alkylating a corresponding compound of formula I in which each of R^(a)and R^(b) is hydrogen; (E) for a compound of formula I in which R^(a) ismethyl or (1-3C) normal alkyl, alkylating a corresponding compound offormula I in which R^(a) is hydrogen; (F) for a compound of formula I inwhich R^(b) is formyl, formylating a corresponding compound of formula Iin which R^(b) is hydrogen; (G) alkylating the phenolic oxygen of acompound of formula X,

using a corresponding compound of formula XI (in which R^(a) as hydrogenmay be replaced by a nitrogen protecting group R^(p)),Y—(CH₂)_(i)-Q-(CH₂)_(j)—NR^(a)R^(b)  XI wherein Y is a conventionalleaving group for nucleophilic substitution and wherein, for a compoundof formula I in which i is 0, the stereochemistry of the carbon to whichY is attached is inverted from that of the product; (H) for a compoundof formula I in which L is carbonyl and R² is —NR^(d)R^(e) or —OR^(f)and L is carbonyl, substitution of the group Y^(c) of a compound offormula XII

(in which R^(a) as hydrogen may be replaced by a nitrogen protectinggroup R^(p)), wherein Y^(c) is a leaving group for nucleophilic aromaticsubstitution, using H—NR^(d)R^(e) or H—OR^(f) or the deprotonated formthereof; and (I) for a compound of formula I in which R² is —OR^(f),alkylating the phenolic oxygen of a compound of formula XIII (in whichR^(a) as hydrogen may be replaced by a nitrogen protecting group R^(p)),

using a corresponding compound of formula Y—R^(f) in which Y is aconventional leaving group for nucleophilic substitution; whereafter,for any of the above procedures, when a functional group is protectedusing a protecting group, removing the protecting group; whereafter, forany of the above procedures, when a pharmaceutically acceptable salt ofa compound of formula I is required, it is obtained by reacting thebasic form of a basic compound of formula I with an acid affording aphysiologically acceptable counterion or by any other conventionalprocedure; and wherein, unless otherwise specified above in this claim,A³-A⁶, L, R, R¹, R², Q, R^(a)-R^(i), i, j and k have any of the valuesdefined in claim
 1. 21. (canceled)
 22. (canceled)
 23. (canceled) 24.(canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)